{ "metadata": { "source": "PubMed (NCBI E-utilities)", "query": "(Glioblastoma[Title/Abstract]) AND (\"Standard of Care\"[Title/Abstract] OR \"Phase 3\"[Title/Abstract] OR \"Clinical Trial\"[Title/Abstract] OR \"Failed\"[Title/Abstract])", "date_range": "2021/01/01 to 2026/12/31", "fetch_date": "2026-01-22T18:34:03.739931", "total_articles": 198 }, "articles": [ { "pmid": "36394838", "title": "Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.", "abstract": "IMPORTANCE: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. OBJECTIVE: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. INTERVENTIONS: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. MAIN OUTCOMES AND MEASURES: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. RESULTS: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). CONCLUSIONS AND RELEVANCE: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00045968.", "journal": "JAMA oncology", "publication_date": "2023-01", "doi": "10.1001/jamaoncol.2022.5370", "authors": [ "Linda M Liau", "Keyoumars Ashkan", "Steven Brem", "Jian L Campian", "John E Trusheim" ], "keywords": [ "Prospective Studies", "Recurrence", "Vaccination", "Glioblastoma", "Humans", "Dendritic Cells", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "36898379", "title": "Transcriptome analysis reveals tumor microenvironment changes in glioblastoma.", "abstract": "A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.", "journal": "Cancer cell", "publication_date": "2023-03-09", "doi": "10.1016/j.ccell.2023.02.019", "authors": [ "Youri Hoogstrate", "Kaspar Draaisma", "Santoesha A Ghisai", "Levi van Hijfte", "Nastaran Barin" ], "keywords": [ "extracellular matrix", "Gene Expression Profiling", "glioblastoma", "tumor evolution", "single-nucleus RNA-seq", "pericytes", "RNA-seq", "neurons", "Glioblastoma", "Tumor Microenvironment", "Humans", "Transcriptome", "recursive correlation", "Neoplasm Recurrence, Local", "Brain Neoplasms" ] }, { "pmid": "35135556", "title": "Glioma targeted therapy: insight into future of molecular approaches.", "abstract": "Gliomas are the common type of brain tumors originating from glial cells. Epidemiologically, gliomas occur among all ages, more often seen in adults, which males are more susceptible than females. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), standard of care and prognosis of gliomas can be dramatically different. Generally, circumscribed gliomas are usually benign and recommended to early complete resection, with chemotherapy if necessary. Diffuse gliomas and other high-grade gliomas according to their molecule subtype are slightly intractable, with necessity of chemotherapy. However, for glioblastoma, feasible resection followed by radiotherapy plus temozolomide chemotherapy define the current standard of care. Here, we discuss novel feasible or potential targets for treatment of gliomas, especially IDH-wild type glioblastoma. Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failure due to complex regulatory network. There is ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor associated macrophage, dendritic cell vaccine, CAR-T), tumor microenvironment, and combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options.", "journal": "Molecular cancer", "publication_date": "2022-02-08", "doi": "10.1186/s12943-022-01513-z", "authors": [ "Keyang Yang", "Zhijing Wu", "Hao Zhang", "Nan Zhang", "Wantao Wu" ], "keywords": [ "Male", "Mutation", "Adult", "Tumor Microenvironment", "Prognosis", "Female", "Glioblastoma", "Humans", "Glioma", "Brain Neoplasms" ] }, { "pmid": "38438346", "title": "Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis.", "abstract": "Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.", "journal": "Signal transduction and targeted therapy", "publication_date": "2024-03-04", "doi": "10.1038/s41392-024-01763-x", "authors": [ "Yuanliang Yan", "Shangjun Zhou", "Xi Chen", "Qiaoli Yi", "Songshan Feng" ], "keywords": [ "Proteomics", "Animals", "Homeostasis", "Mice", "Ubiquitin-Protein Ligases", "Reactive Oxygen Species", "Glioblastoma", "Humans", "Disease Models, Animal", "Glioma", "Temozolomide" ] }, { "pmid": "39406966", "title": "Immunotherapy for glioblastoma: current state, challenges, and future perspectives.", "abstract": "Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.", "journal": "Cellular & molecular immunology", "publication_date": "2024-10-15", "doi": "10.1038/s41423-024-01226-x", "authors": [ "Yang Liu", "Fei Zhou", "Heba Ali", "Justin D Lathia", "Peiwen Chen" ], "keywords": [ "Immunotherapy combination", "Animals", "Immunotherapy", "Immune checkpoint inhibitors (ICIs)", "Adoptive T-cell therapies", "Oncolytic viral therapies", "Tumor vaccines", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "39304781", "title": "High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity.", "abstract": "Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.", "journal": "Nature medicine", "publication_date": "2024-09-20", "doi": "10.1038/s41591-024-03224-y", "authors": [ "Sohyon Lee", "Tobias Weiss", "Marcel Bühler", "Julien Mena", "Zuzanna Lottenbach" ], "keywords": [ "Animals", "Mice", "High-Throughput Screening Assays", "Glioblastoma", "Humans", "Cell Line, Tumor", "Drug Repositioning", "Brain Neoplasms", "Antineoplastic Agents" ] }, { "pmid": "34731610", "title": "Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.", "abstract": "The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.", "journal": "Cell reports", "publication_date": "2021-11", "doi": "10.1016/j.celrep.2021.109957", "authors": [ "Junfeng Bi", "Atif Khan", "Jun Tang", "Aaron M Armando", "Sihan Wu" ], "keywords": [ "fluoxetine", "Animals", "Tumor Burden", "Electronic Health Records", "SMPD1", "glioblastoma", "EGFR signaling", "Glioblastoma", "Humans", "Sphingomyelin Phosphodiesterase", "Membrane lipids", "sphingolipid metabolism", "Signal Transduction", "Antineoplastic Agents", "Retrospective Studies", "Tumor Cells, Cultured", "real-world evidence", "electronic medical records", "Sphingomyelins", "Female" ] }, { "pmid": "38502052", "title": "Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial.", "abstract": "BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier. METHODS: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.", "journal": "Neuro-oncology", "publication_date": "2024-09", "doi": "10.1093/neuonc/noae053", "authors": [ "Patrick Roth", "Thierry Gorlia", "Jaap C Reijneveld", "Filip de Vos", "Ahmed Idbaih" ], "keywords": [ "glioma", "MGMT", "proteasome inhibitor", "Prognosis", "Glioblastoma", "Humans", "EORTC 1709", "Male", "Middle Aged", "Pyrroles", "Female", "DNA Modification Methylases", "randomized study", "Temozolomide", "Adult", "Follow-Up Studies", "Antineoplastic Combined Chemotherapy Protocols", "Aged", "Lactones", "Young Adult" ] }, { "pmid": "39255775", "title": "Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence.", "abstract": "Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.", "journal": "Cancer cell", "publication_date": "2024-09", "doi": "10.1016/j.ccell.2024.08.012", "authors": [ "Spencer S Watson", "Anoek Zomer", "Nadine Fournier", "Joao Lourenco", "Manfredo Quadroni" ], "keywords": [ "Animals", "Receptor, Macrophage Colony-Stimulating Factor", "Mice", "Xenograft Model Antitumor Assays", "Transforming Growth Factor beta", "Glioblastoma", "Tumor Microenvironment", "Humans", "Fibrosis", "Cell Line, Tumor", "Neoplasm Recurrence, Local", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "40346362", "title": "Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.", "abstract": "The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.", "journal": "Nature genetics", "publication_date": "2025-05-09", "doi": "10.1038/s41588-025-02168-4", "authors": [ "Avishay Spitzer", "Kevin C Johnson", "Masashi Nomura", "Luciano Garofano", "Djamel Nehar-Belaid" ], "keywords": [ "Isocitrate Dehydrogenase", "Longitudinal Studies", "Male", "Genomics", "Middle Aged", "Glioblastoma", "Tumor Microenvironment", "Humans", "Female", "Neoplasm Recurrence, Local", "Single-Cell Analysis", "Brain Neoplasms" ] }, { "pmid": "33602305", "title": "Current status and recent advances in reirradiation of glioblastoma.", "abstract": "Despite aggressive management consisting of maximal safe surgical resection followed by external beam radiation therapy (60 Gy/30 fractions) with concomitant and adjuvant temozolomide, approximately 90% of WHO grade IV gliomas (glioblastomas, GBM) will recur locally within 2 years. For patients with recurrent GBM, no standard of care exists. Thanks to the continuous improvement in radiation science and technology, reirradiation has emerged as feasible approach for patients with brain tumors. Using stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT), either hypofractionated or conventionally fractionated schedules, several studies have suggested survival benefits following reirradiation of patients with recurrent GBM; however, there are still questions to be answered about the efficacy and toxicity associated with a second course of radiation. We provide a clinical overview on current status and recent advances in reirradiation of GBM, addressing relevant clinical questions such as the appropriate patient selection and radiation technique, optimal dose fractionation, reirradiation tolerance of the brain and the risk of radiation necrosis.", "journal": "Radiation oncology (London, England)", "publication_date": "2021-02-18", "doi": "10.1186/s13014-021-01767-9", "authors": [ "Giuseppe Minniti", "Maximilian Niyazi", "Filippo Alongi", "Piera Navarria", "Claus Belka" ], "keywords": [ "Radiation Injuries", "Hypofractionated radiotherapy", "Target delineation", "Re-Irradiation", "Recurrent glioblastoma", "Radiosurgery", "Radionecrosis", "Prognosis", "Reirradiation", "Dose Fractionation, Radiation", "Glioblastoma", "Survival Analysis", "Humans", "Stereotactic radiosurgery", "Neoplasm Recurrence, Local", "Brain Neoplasms" ] }, { "pmid": "36959214", "title": "STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma.", "abstract": "As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma.", "journal": "Nature communications", "publication_date": "2023-03-23", "doi": "10.1038/s41467-023-37328-9", "authors": [ "Peng Zhang", "Aida Rashidi", "Junfei Zhao", "Caylee Silvers", "Hanxiang Wang" ], "keywords": [ "Animals", "CD47 Antigen", "Mice", "Interferons", "Glioblastoma", "B7-H1 Antigen", "Humans", "Nanoparticles", "Brain Neoplasms" ] }, { "pmid": "39480453", "title": "Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma: A Randomized Clinical Trial.", "abstract": "IMPORTANCE: The prognosis for patients with glioblastoma is poor following standard therapy with surgical resection, radiation, temozolomide, and tumor-treating fields. OBJECTIVES: To evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant chemosensitizing effects of the polyadenosine diphosphate-ribose polymerase 1/2 inhibitor veliparib when combined with temozolomide. DESIGN, SETTING, AND PARTICIPANTS: Patients with newly diagnosed glioblastoma with MGMT promoter hypermethylation who had completed concomitant radiation and temozolomide were enrolled between December 15, 2014, and December 15, 2018, in this Alliance for Clinical Trials in Oncology trial. The data for this analysis were locked on April 21, 2023. INTERVENTIONS: Patients were randomized and treated with standard adjuvant temozolomide (150-200 mg/m2 orally, days 1-5) combined with either placebo or veliparib (40 mg orally, twice daily, days 1-7) for 6 cycles. MAIN OUTCOMES AND MEASURES: The primary end point for the phase 3 portion of the trial was overall survival (OS). RESULTS: There were 322 patients randomized during the phase 2 accrual period and an additional 125 patients randomized to complete the phase 3 accrual, for a total of 447 patients in the final phase 3 analysis. The median (range) age for patients was 60 (20-85) years and 190 patients (42.5%) were female. The median OS was 24.8 months (90% CI, 22.6-27.7) for the placebo arm and 28.1 months (90% CI, 24.3-33.3) for the veliparib arm (P = .17). The difference in survival did not meet the prespecified efficacy end point. However, there was a separation of the survival curves that favored the veliparib arm over 24 to 48 months of follow-up. The experimental combination was well tolerated with an acceptable elevation in grade 3 or 4 hematologic toxic effects. CONCLUSIONS AND RELEVANCE: This trial found that adding veliparib to adjuvant temozolomide did not significantly extend OS in patients with newly diagnosed, MGMT-hypermethylated glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02152982.", "journal": "JAMA oncology", "publication_date": "2024-12", "doi": "10.1001/jamaoncol.2024.4361", "authors": [ "Jann N Sarkaria", "Karla V Ballman", "Sani H Kizilbash", "Erik P Sulman", "Caterina Giannini" ], "keywords": [ "Male", "Adult", "DNA Repair Enzymes", "Middle Aged", "Antineoplastic Combined Chemotherapy Protocols", "Aged", "DNA Modification Methylases", "Treatment Outcome", "Tumor Suppressor Proteins", "Female", "Glioblastoma", "Humans", "DNA Methylation", "Benzimidazoles", "Aged, 80 and over", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "40016450", "title": "Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma.", "abstract": "Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).", "journal": "Nature medicine", "publication_date": "2025-02-27", "doi": "10.1038/s41591-025-03512-1", "authors": [ "Georgina V Long", "Elena Shklovskaya", "Laveniya Satgunaseelan", "Yizhe Mao", "Inês Pires da Silva" ], "keywords": [ "Immunotherapy", "Lymphocytes, Tumor-Infiltrating", "Tumor Microenvironment", "Immune Checkpoint Inhibitors", "Programmed Cell Death 1 Receptor", "Glioblastoma", "Neoadjuvant Therapy", "Humans", "Brain Neoplasms" ] }, { "pmid": "38507470", "title": "Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.", "abstract": "Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.", "journal": "Science translational medicine", "publication_date": "2024-03-20", "doi": "10.1126/scitranslmed.adg5553", "authors": [ "Jianxing Yin", "Xin Ge", "Fangshu Ding", "Liuguijie He", "Keying Song" ], "keywords": [ "Neoplastic Stem Cells", "Fumarates", "Iron", "Sulfur", "Glioblastoma", "Humans", "Cell Line, Tumor", "PTEN Phosphohydrolase", "Glioma", "Brain Neoplasms" ] }, { "pmid": "39560080", "title": "Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses.", "abstract": "BACKGROUND: Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown. METHODS: Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses. RESULTS: While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes. CONCLUSIONS: Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.", "journal": "Neuro-oncology", "publication_date": "2025-01", "doi": "10.1093/neuonc/noae214", "authors": [ "Calixto-Hope G Lucas", "Nadeem N Al-Adli", "Jacob S Young", "Rohit Gupta", "Ramin A Morshed" ], "keywords": [ "Mutation", "glioblastoma", "Prognosis", "Glioblastoma", "Humans", "Male", "Middle Aged", "DNA methylation", "Epigenesis, Genetic", "molecular neuropathology", "Female", "DNA Methylation", "gliosarcoma", "Adult", "Biomarkers, Tumor", "Follow-Up Studies", "Aged", "Phenotype", "Isocitrate Dehydrogenase", "temozolomide-induced hypermutation" ] }, { "pmid": "33781503", "title": "Novel Radiation Approaches.", "abstract": "The standard of care treatment for glioblastoma is surgical resection followed by radiotherapy to 60 Gy with concurrent and adjuvant temozolomide with or without tumor-treating fields. Advanced imaging techniques are under evaluation to better guide radiotherapy target volume delineation and allow for dose escalation. Particle therapy, in the form of protons, carbon ions, and boron neutron capture therapy, are being assessed as strategies to improve the radiotherapeutic ratio. Stereotactic, hypofractionated, pulsed-reduced dose-rate, and particle radiotherapy are re-irradiation techniques each uniquely suited for different clinical scenarios. Novel radiotherapy approaches, such as FLASH, represent promising advancements in radiotherapy for glioblastoma.", "journal": "Neurosurgery clinics of North America", "publication_date": "2021-04", "doi": "10.1016/j.nec.2020.12.007", "authors": [ "Rupesh Kotecha", "Martin C Tom", "Minesh P Mehta" ], "keywords": [ "Radiation therapy", "Trials", "GBM", "Carbon ions", "Protons", "Glioblastoma", "Humans", "Radiotherapy", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "33223020", "title": "Radiosurgery for Glioblastoma.", "abstract": "Glioblastoma (GBM) is infiltrative neoplasm with limited treatment options and poor overall survival. Stereotactic radiosurgery (SRS) allows spatially precise and conformal delivery of high doses of radiation. Salvage SRS for locally recurrent GBM was shown to improve patient survival and have more favorable safety profile than repeated surgical resection. Boost SRS after fractionated radiation therapy is sometimes attempted; however, Radiation Therapy Oncology Group 93-05 randomized clinical trial did not demonstrate benefits of upfront SRS that was administered before fractionated radiation. Administration of bevacizumab with SRS is associated with improved survival and can allow SRS dose escalation.", "journal": "Neurosurgery clinics of North America", "publication_date": "2020-11-05", "doi": "10.1016/j.nec.2020.08.007", "authors": [ "Adomas Bunevicius", "Jason P Sheehan" ], "keywords": [ "Survival", "Radiosurgery", "Treatment Outcome", "Prognosis", "Glioblastoma", "Gamma knife radiosurgery", "Humans", "Stereotactic radiosurgery", "Neoplasm Recurrence, Local", "Brain Neoplasms" ] }, { "pmid": "34101090", "title": "Contemporary RNA Therapeutics for Glioblastoma.", "abstract": "Glioblastoma (GBM) is the most common primary brain tumor in adults and is universally lethal with a median survival of less than two years with standard therapy. RNA-based immunotherapies have significant potential to establish a durable treatment response for malignant brain tumors including GBM. RNA offers clear advantages over antigen-focused approaches but cannot often be directly administered due to biological instability. This review will focus on utilization of RNA dendritic cell vaccines and RNA nanoparticle therapies in the treatment of GBM. RNA-pulsed dendritic cell vaccines have been shown to be safe in a small phase I clinical trial and RNA-loaded nanoparticle vaccines will soon be underway in GBM patients (NCT04573140).", "journal": "Neuromolecular medicine", "publication_date": "2021-06-08", "doi": "10.1007/s12017-021-08669-9", "authors": [ "Kaitlyn Melnick", "Farhad Dastmalchi", "Duane Mitchell", "Maryam Rahman", "Elias J Sayour" ], "keywords": [ "Immunotherapy", "Nanoparticles", "RNA", "Adult", "Dendritic cells", "Vaccine", "Cancer Vaccines", "Clinical Trials, Phase I as Topic", "Glioblastoma", "Humans", "Dendritic Cells", "Brain Neoplasms" ] }, { "pmid": "34665646", "title": "New Approaches to Glioblastoma.", "abstract": "Faced with unique immunobiology and marked heterogeneity, treatment strategies for glioblastoma require therapeutic approaches that diverge from conventional oncological strategies. The selection and prioritization of targeted and immunotherapeutic strategies will need to carefully consider these features and companion biomarkers developed alongside treatment strategies to identify the appropriate patient populations. Novel clinical trial strategies that interrogate the tumor microenvironment for drug penetration and target engagement will inform go/no-go later-stage clinical studies. Innovative trial designs and analyses are needed to move effective agents toward regulatory approvals more rapidly.", "journal": "Annual review of medicine", "publication_date": "2021-10-19", "doi": "10.1146/annurev-med-042420-102102", "authors": [ "Mustafa Khasraw", "Yoko Fujita", "Catalina Lee-Chang", "Irina V Balyasnikova", "Hinda Najem" ], "keywords": [ "Immunotherapy", "glioblastoma", "immunotherapy", "precision medicine", "Glioblastoma", "Tumor Microenvironment", "Humans", "Biomarkers", "Brain Neoplasms" ] }, { "pmid": "34092564", "title": "[Chemotherapy for Glioma].", "abstract": "Chemotherapeutic treatment of malignant gliomas is extremely challenging. Tumor accumulation of systemically-administrated chemotherapy is always hindered by the blood-brain barrier(BBB). Although temozolomide administered orally or intravenously represents the standard of care for malignant gliomas, its efficacy is unsatisfactory. Local chemotherapy bypasses the BBB and, therefore, achieves a high drug concentration at the site the drug is administered. Carmustine wafers are clinically available local chemotherapeutic agents. However, their efficacy is limited because of limited drug penetration into the tumor. Combined with the highly chemoresistant features of glioma itself, ongoing chemotherapy is far from satisfactory in terms of efficacy. This review covers several important issues regarding temozolomide chemotherapy, including the reactivation of hepatitis B virus, assessment of MGMT promoter methylation, and pseudo-progression. Local chemotherapy for newly diagnosed resectable glioblastoma cases using carmustine wafers is currently under investigation with a randomized phase 3 trial (JCOG 1703), which will also be discussed. In addition, recent progress in convection-enhanced delivery of chemotherapeutics against gliomas has also been reported. Development of an alternative strategy to effectively deliver drugs to the tumor site may improve the efficacy of chemotherapy against gliomas in the near future.", "journal": "No shinkei geka. Neurological surgery", "publication_date": "2021-05", "doi": "10.11477/mf.1436204432", "authors": [ "Ryuta Saito" ], "keywords": [ "Clinical Trials, Phase III as Topic", "Randomized Controlled Trials as Topic", "Antineoplastic Combined Chemotherapy Protocols", "Glioblastoma", "Humans", "Glioma", "Brain Neoplasms", "Antineoplastic Agents" ] }, { "pmid": "33753869", "title": "Engineered cells as glioblastoma therapeutics.", "abstract": "In spite of significant recent advances in our understanding of the genetics and cell biology of glioblastoma, to date, this has not led to improved treatments for this cancer. In addition to small molecule, antibody, and engineered virus approaches, engineered cells are also being explored as glioblastoma therapeutics. This includes CAR-T cells, CAR-NK cells, as well as engineered neural stem cells and mesenchymal stem cells. Here we review the state of this field, starting with clinical trial studies. These have established the feasibility and safety of engineered cell therapies for glioblastoma and show some evidence for activity. Next, we review the preclinical literature and compare the strengths and weaknesses of various starting cell types for engineered cell therapies. Finally, we discuss future directions for this nascent but promising modality for glioblastoma therapy.", "journal": "Cancer gene therapy", "publication_date": "2021-03-22", "doi": "10.1038/s41417-021-00320-w", "authors": [ "Aparna Ramanathan", "Ian A J Lorimer" ], "keywords": [ "Humans", "Cell- and Tissue-Based Therapy", "Glioblastoma" ] }, { "pmid": "36196416", "title": "Glioblastoma - treatment and obstacles.", "abstract": "BACKGROUND: Glioblastoma is the most common and aggressive primary tumor in adults. A narrative review of all the relevant papers known was conducted. MATERIALS AND METHODS: Reviews, clinical trials, and randomized controlled trials published from 1981 through September 2021 and written, or at least abstracted, in English were analyzed. RESULTS: The standard of care for glioblastoma is the maximum safe resection possible, followed by radiation therapy and concurrent temozolomide (TMZ) and daily TMZ and tumor treatment fields (TTFields) after irradiation. There is no evidence to date of the benefit of brachytherapy, radiosurgery (SRS), fractional stereotactic radiotherapy (FSRT), and hyperfractionated radiotherapy over conventional external beam radiation therapy (EBRT) for the primary tumor. The assessment of age and performance status before treatment in the elderly enables hypofractionated radiotherapy. The research of tumor molecular signatures contributes to the choice of the best-targeted drug therapy. In recurrent glioblastoma, it is necessary to balance the risks and benefits of re-radiation and association with bevacizumab. Solid data confirming the role of immunotherapy in the treatment of malignant glioma are still lacking. CONCLUSIONS: Although the treatment of glioblastoma has evolved in terms of local control, mortality remains close to 12 months after diagnosis. To obtain better results and reduce recurrence, future research needs to investigate the frontiers of knowledge, such as the elucidation of the molecular mechanisms related to the tumor, the optimization of drugs to overcome the blood-brain barrier effectively, and the discovery of new therapies aimed at the heterogeneous profile of this neoplasm.", "journal": "Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology", "publication_date": "2022-09-19", "doi": "10.5603/RPOR.a2022.0076", "authors": [ "Farley Soares Cantidio", "Gabriel Oliveira Bernardes Gil", "Izabella Nobre Queiroz", "Marcos Regalin" ], "keywords": [ "radiation therapy", "glioblastoma", "temozolomide", "malignant glioma" ] }, { "pmid": "33781508", "title": "Targeting Glioma Stem Cells.", "abstract": "Only a small fraction of the tumor cell population, glioma-initiating cells (GICs) help glioblastoma propagate, invade, evade immune recognition, repair DNA in response to radiation more efficiently, remodel the microenvironment for optimal growth, and actively pump out chemotherapies. Recent data hint that efforts toward GIC characterization and quantification can help predict patient outcomes, and yet the different subpopulations of GICs remain incompletely understood. A better understanding of GIC subtypes and functions proves critical for engineering targeted therapies. Challenges for doing so are discussed, and dopamine receptor antagonists are introduced as new means to enhance the efficacy of the current standard-of-care against GICs.", "journal": "Neurosurgery clinics of North America", "publication_date": "2021-02-18", "doi": "10.1016/j.nec.2021.01.002", "authors": [ "Yagmur Muftuoglu", "Frank Pajonk" ], "keywords": [ "Intratumoral heterogeneity", "Neoplastic Stem Cells", "Plasticity", "Glioblastoma", "Tumor Microenvironment", "Humans", "Glioblastoma-initiating cells", "Glioma", "Brain Neoplasms" ] }, { "pmid": "40136656", "title": "Angiogenesis in Glioblastoma-Treatment Approaches.", "abstract": "Glioblastoma, the most common primary malignant brain tumor in adults, carries a poor prognosis, with a median survival of just 15 months, significantly impacting patients' quality of life. The aggressive growth of these highly vascularized tumors relies heavily on angiogenesis, driven primarily by vascular endothelial growth factor-A. Therefore, VEGF signaling pathway has become a prime therapeutic target in GBM treatment over the past decade. While anti-angiogenic treatment showed promise, agents like bevacizumab have ultimately failed to improve overall survival. This highlights the presence of compensatory angiogenic mechanisms that bypass VEGF inhibition, necessitating further investigation into resistance mechanisms and the development of more effective therapeutic strategies. This review examined the current landscape of anti-angiogenic agents for GBM, analyzed the mechanisms driving resistance to these therapies, and explored potential strategies for enhancing their effectiveness.", "journal": "Cells", "publication_date": "2025-03-11", "doi": "10.3390/cells14060407", "authors": [ "Agnieszka Nowacka", "Maciej Śniegocki", "Wojciech Smuczyński", "Dominika Bożiłow", "Ewa Ziółkowska" ], "keywords": [ "tumor microenvironment", "Animals", "Angiogenesis", "angiogenesis", "GBM", "VEGF", "Neovascularization, Pathologic", "anti-angiogenic therapy", "bevacizumab", "glioblastoma", "resistance", "Angiogenesis Inhibitors", "Glioblastoma", "Humans", "Vascular Endothelial Growth Factor A", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "35806212", "title": "Glioblastoma Treatment: State-of-the-Art and Future Perspectives.", "abstract": "(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research.", "journal": "International journal of molecular sciences", "publication_date": "2022-06-29", "doi": "10.3390/ijms23137207", "authors": [ "Alejandro Rodríguez-Camacho", "José Guillermo Flores-Vázquez", "Júlia Moscardini-Martelli", "Jorge Alejandro Torres-Ríos", "Alejandro Olmos-Guzmán" ], "keywords": [ "radiotherapy", "Temozolomide", "neurosurgery", "glioblastoma", "Bevacizumab", "temozolomide", "target therapy", "immunotherapy", "Glioblastoma", "Humans", "Brain Neoplasms", "Dacarbazine" ] }, { "pmid": "32253714", "title": "A review of glioblastoma immunotherapy.", "abstract": "INTRODUCTION: Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy. METHODS: Literature search was performed on PubMed between 1961 and 2020. RESULTS: Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma's highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction. CONCLUSIONS: Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.", "journal": "Journal of neuro-oncology", "publication_date": "2020-04-06", "doi": "10.1007/s11060-020-03448-1", "authors": [ "Ravi Medikonda", "Gavin Dunn", "Maryam Rahman", "Peter Fecci", "Michael Lim" ], "keywords": [ "Immunotherapy", "GBM Immunotherapy", "Glioblastoma", "Carcinoma, Non-Small-Cell Lung", "Humans", "Lung Neoplasms", "Neoplasm Recurrence, Local", "Brain Neoplasms" ] }, { "pmid": "36900311", "title": "Metabolic Barriers to Glioblastoma Immunotherapy.", "abstract": "Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.", "journal": "Cancers", "publication_date": "2023-02-28", "doi": "10.3390/cancers15051519", "authors": [ "Nikita Choudhary", "Robert C Osorio", "Jun Y Oh", "Manish K Aghi" ], "keywords": [ "tumor microenvironment", "metabolism", "glutamine metabolism", "glioblastoma", "lipid metabolism", "tryptophan metabolism", "glycolysis", "immunotherapy" ] }, { "pmid": "36011015", "title": "Next Steps for Immunotherapy in Glioblastoma.", "abstract": "Outcomes for glioblastoma (GBM) patients undergoing standard of care treatment remain poor. Here we discuss the portfolio of previously investigated immunotherapies for glioblastoma, including vaccine therapy and checkpoint inhibitors, as well as novel emerging therapeutic approaches. In addition, we explore the factors that potentially influence response to immunotherapy, which should be considered in future research aimed at improving immunotherapy efficacy.", "journal": "Cancers", "publication_date": "2022-08-20", "doi": "10.3390/cancers14164023", "authors": [ "Toni Q Cao", "Derek A Wainwright", "Catalina Lee-Chang", "Jason Miska", "Adam M Sonabend" ], "keywords": [ "immunotherapy", "glioblastoma", "immune system" ] }, { "pmid": "39469854", "title": "The challenges and clinical landscape of glioblastoma immunotherapy.", "abstract": "Glioblastoma is associated with a dismal prognosis with the standard of care involving surgery, radiation therapy and temozolomide chemotherapy. This review investigates the features that make glioblastoma difficult to treat and the results of glioblastoma immunotherapy clinical trials so far. There have been over a hundred clinical trials involving immunotherapy in glioblastoma. We report the survival-related outcomes of every Phase III glioblastoma immunotherapy trial with online published results we could find at the time of writing. To date, the DCVax-L vaccine is the only immunotherapy shown to have statistically significant increased median survival compared with standard-of-care in a Phase III trial: 19.3 months versus 16.5 months. However, this trial used an external control group to compare with the intervention which limits its quality of evidence. In conclusion, glioblastoma immunotherapy requires further investigation to determine its significance in improving disease survival.", "journal": "CNS oncology", "publication_date": "2024-10-29", "doi": "10.1080/20450907.2024.2415878", "authors": [ "Andrew Timothy Ng", "Tyler Steve", "Kevin T Jamouss", "Abdul Arham", "Sarah Kawtharani" ], "keywords": [ "Clinical Trials, Phase III as Topic", "Immunotherapy", "glioblastoma", "clinical trials", "immunotherapy", "cancer vaccines", "Glioblastoma", "Humans", "clinical research", "Brain Neoplasms", "drug resistance" ] }, { "pmid": "37742885", "title": "Targeting androgen receptor in glioblastoma.", "abstract": "Glioblastomas are primary brain tumors that originate from glial stem cells or progenitor cells. There is a large difference in the incidence of glioblastoma between males and females. Studies revealed that the gender differences in the tumor may be attributable to the androgen receptor signaling axis. The incidence rate of glioblastoma in men is higher than that in women. Aberrant activation of the androgen receptor signaling pathway, or interactions between the androgen receptor signaling axis and other signaling axes promote the development of glioblastoma. Therefore, targeting the androgen receptor holds promise as a therapeutic approach for glioblastoma. This review investigates the dynamics of drug research into the treatment of glioblastoma by targeting the androgen receptor. The first finding in line with expectations is that androgen receptor antagonists, represented by enzalutamide, have been studied and shown to have anti-glioblastoma effects. In addition, it was found that the combination of 5-alpha reductase inhibitors and androgen receptor antagonists resulted in better therapeutic outcomes than each of them alone. Similar results were obtained with the combination of an epidermal growth factor receptor inhibitor and an androgen receptor antagonist. In addition, four small molecule compounds have been shown to exert significant anti-glioblastoma effects by directly or indirectly targeting the androgen receptor. Expectantly, one of these small molecules, seviteronel, progressed to the phase II clinical trial stage. These findings suggest that targeting the androgen receptor for glioblastoma may be a promising therapeutic option.", "journal": "Critical reviews in oncology/hematology", "publication_date": "2023-09-24", "doi": "10.1016/j.critrevonc.2023.104142", "authors": [ "Xia Gan", "Yonghong Liu", "Xueni Wang" ], "keywords": [ "Epidermal growth factor receptor", "5α-Reductase inhibitor", "5α-Reductase", "Androgen receptor antagonists", "Androgen receptor", "Glioblastoma" ] }, { "pmid": "39293549", "title": "Glutaminase 2 as a therapeutic target in glioblastoma.", "abstract": "Glioblastoma (GBM) is the most common malignant primary adult brain tumor. Despite standard-of-care treatment, which consists of surgical resection, temozolomide (TMZ) treatment, and radiotherapy, the prognosis for GBM patients remains poor with a five-year survival rate of 5 %. With treatment, the median survival time is 14 months, suggesting the dire need for new, more effective therapies. Glutaminolysis, the metabolic pathway by which cells can convert glutamine to ATP, is essential for the survival of GBM cells and represents a putative target for treatment. Glutamine replenishes tricarboxylic acid (TCA) cycle intermediates through glutaminolysis. The first step of glutaminolysis, the deamination of glutamine, can be carried out by either glutaminase 1 (GLS) or glutaminase 2 (GLS2). However, it is becoming increasingly clear that these enzymes have opposing functions in GBM; GLS induces deamination of glutamine, thereby acting in an oncogenic fashion, while GLS2 has non-enzymatic, tumor-suppressive functions that are repressed in GBM. In this review, we explore the important role of glutaminolysis and the opposing roles of GLS and GLS2 in GBM. Further, we provide a detailed discussion of GLS2's newly discovered non-enzymatic functions that can be targeted in GBM. We conclude by considering therapeutic approaches that have emerged from the understanding of GLS and GLS2's opposing roles in GBM.", "journal": "Biochimica et biophysica acta. Reviews on cancer", "publication_date": "2024-09-16", "doi": "10.1016/j.bbcan.2024.189182", "authors": [ "Rithvik K Veeramachaneni", "Robert K Suter", "Emma Rowland", "Anna Jermakowicz", "Nagi G Ayad" ], "keywords": [ "Molecular Targeted Therapy", "Animals", "Warburg effect", "Glutaminolysis", "Glutaminase", "Tumor suppression", "Glutamine", "Glioblastoma", "Humans", "Brain Neoplasms" ] }, { "pmid": "33864598", "title": "Sex Differences in Glioblastoma Immunotherapy Response.", "abstract": "Glioblastoma (GBM), the most common primary malignant brain tumor, remains difficult to treat and shares phenotypes, including an aberrant immune response, with other neurological disorders. Understanding the cellular and molecular mechanisms underlying this pathological immune response remains a priority, particularly as standard of care for advanced cancers evolves to include immunotherapies, which have yet to show strong clinical efficacy in GBM. Epidemiological evidence supports a sex difference in GBM, with increased prevalence in males, and recent studies identified differences between males and females ranging from genetic aberrations to cellular programs. Sex differences have also been identified in immune response, and in this mini-review, we present these differences to highlight potential sex-specific cellular and molecular mechanisms that underly GBM growth and response to immunotherapies. These sex differences offer an opportunity to understand GBM pathogenesis and extend beyond GBM to other tumors and neurological disorders to inform the development of next-generation therapies.", "journal": "Neuromolecular medicine", "publication_date": "2021-04-17", "doi": "10.1007/s12017-021-08659-x", "authors": [ "Juyeun Lee", "Kristen Kay", "Katie Troike", "Manmeet S Ahluwalia", "Justin D Lathia" ], "keywords": [ "Immune system", "Immunotherapy", "Male", "Sex differences", "Sex Characteristics", "Treatment Outcome", "Female", "Glioblastoma", "Humans", "Glioma", "Brain Neoplasms" ] }, { "pmid": "35454848", "title": "Emerging Biomarkers for Immunotherapy in Glioblastoma.", "abstract": "Immunotherapy has shown clinical benefits in several solid malignancies-in particular, melanoma and non-small cell lung cancer. However, in other solid tumours such as glioblastoma (GBM), the response to immunotherapy has been more variable, and except for anti-PD-1 for patients with microsatellite instable (MSI)+ cancers, no immunotherapy is currently approved for GBM patients. GBM is the most common and most aggressive brain cancer with a very poor prognosis and a median overall survival of 15 months. A few prognostic biomarkers have been identified and are used to some extent, but apart from MSI, no biomarkers are used for patient stratification for treatments other than the standard of care, which was established 15 years ago. Around 25% of new treatments investigated in GBM are immunotherapies. Recent studies indicate that the use of integrated and validated immune correlates predicting the response and guiding treatments could improve the efficacy of immunotherapy in GBM. In this review, we will give an overview of the current status of immunotherapy and biomarkers in use in GBM with the main challenges of treatment in this disease. We will also discuss emerging biomarkers that could be used in future immunotherapy strategies for patient stratification and potentially improved treatment efficacy.", "journal": "Cancers", "publication_date": "2022-04-12", "doi": "10.3390/cancers14081940", "authors": [ "Nadia Mensali", "Else Marit Inderberg" ], "keywords": [ "tumour infiltrating lymphocytes", "immunoprofiling", "glioblastoma", "immunotherapy", "biomarkers" ] }, { "pmid": "38994761", "title": "Targeting drug resistance in glioblastoma (Review).", "abstract": "Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor‑treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood‑brain barrier, blood tumor barrier, glioma stem‑like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.", "journal": "International journal of oncology", "publication_date": "2024-07-12", "doi": "10.3892/ijo.2024.5668", "authors": [ "Jonathan H Sherman", "Adam Bobak", "Tasneem Arsiwala", "Paul Lockman", "Sonikpreet Aulakh" ], "keywords": [ "Blood-Brain Barrier", "Molecular Targeted Therapy", "radiation therapy", "Neoplastic Stem Cells", "glioblastoma", "recurrence", "genetic heterogeneity", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "therapeutics", "Brain Neoplasms", "resistance" ] }, { "pmid": "38479191", "title": "Advancing glioblastoma treatment by targeting metabolism.", "abstract": "Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.", "journal": "Neoplasia (New York, N.Y.)", "publication_date": "2024-03-12", "doi": "10.1016/j.neo.2024.100985", "authors": [ "Jinyi Zhao", "Xuemei Ma", "Peixian Gao", "Xueqi Han", "Pengxiang Zhao" ], "keywords": [ "Therapy", "Metabolism", "Signaling pathway", "Glioblastoma", "Humans", "Cell Line, Tumor", "Brain Neoplasms" ] }, { "pmid": "33781950", "title": "Accelerating glioblastoma therapeutics via venture philanthropy.", "abstract": "Development of curative treatments for glioblastoma (GBM) has been stagnant in recent decades largely because of significant financial risks. A portfolio-based strategy for the parallel discovery of breakthrough therapies can effectively reduce the financial risks of potentially transformative clinical trials for GBM. Using estimates from domain experts at the National Brain Tumor Society (NBTS), we analyze the performance of a portfolio of 20 assets being developed for GBM, diversified across different development phases and therapeutic mechanisms. We find that the portfolio generates a 14.9% expected annualized rate of return. By incorporating the adaptive trial platform GBM AGILE in our simulations, we show that at least one drug candidate in the portfolio will receive US Food and Drug Administration (FDA) approval with a probability of 79.0% in the next decade.", "journal": "Drug discovery today", "publication_date": "2021-03-27", "doi": "10.1016/j.drudis.2021.03.020", "authors": [ "Kien Wei Siah", "Qingyang Xu", "Kirk Tanner", "Olga Futer", "John J Frishkopf" ], "keywords": [ "Fund Raising", "Computer Simulation", "Biomedical megafund", "Parallel drug discovery", "Models, Theoretical", "Glioblastoma", "Humans", "Adaptive Clinical Trials as Topic", "Adaptive clinical trial platform", "Brain Neoplasms" ] }, { "pmid": "38183840", "title": "Glioblastoma vaccines: past, present, and opportunities.", "abstract": "Glioblastoma (GBM) is one of the most lethal central nervous systems (CNS) tumours in adults. As supplements to standard of care (SOC), various immunotherapies improve the therapeutic effect in other cancers. Among them, tumour vaccines can serve as complementary monotherapy or boost the clinical efficacy with other immunotherapies, such as immune checkpoint blockade (ICB) and chimeric antigen receptor T cells (CAR-T) therapy. Previous studies in GBM therapeutic vaccines have suggested that few neoantigens could be targeted in GBM due to low mutation burden, and single-peptide therapeutic vaccination had limited efficacy in tumour control as monotherapy. Combining diverse antigens, including neoantigens, tumour-associated antigens (TAAs), and pathogen-derived antigens, and optimizing vaccine design or vaccination strategy may help with clinical efficacy improvement. In this review, we discussed current GBM therapeutic vaccine platforms, evaluated and potential antigenic targets, current challenges, and perspective opportunities for efficacy improvement.", "journal": "EBioMedicine", "publication_date": "2024-01-05", "doi": "10.1016/j.ebiom.2023.104963", "authors": [ "Zujian Xiong", "Itay Raphael", "Michael Olin", "Hideho Okada", "Xuejun Li" ], "keywords": [ "Vaccine efficacy", "Immunotherapy", "Adult", "Vaccine platform", "Antigens, Neoplasm", "Cancer Vaccines", "Tumour antigen", "Glioblastoma", "Humans", "Vaccine perspective", "Brain Neoplasms", "Immunotherapy, Adoptive" ] }, { "pmid": "35344682", "title": "Immunotherapy of glioblastoma: Recent advances and future prospects.", "abstract": "Glioblastoma (GBM) stands out as the most common, aggressive form of primary malignant brain tumor conferring a devastatingly poor prognosis. Despite aggressive standard-of-care in surgical resection and chemoradiation with temozolomide, the median overall survival of patients still remains no longer than 15 months, due to significant tumor heterogeneity, immunosuppression induced by the tumor immune microenvironment and low mutational burden. Advances in immunotherapeutic approaches have revolutionized the treatment of various cancer types and become conceptually attractive for glioblastoma. In this review, we provide an overview of the basic knowledge underlying immune targeting and promising immunotherapeutic strategies including CAR T cells, oncolytic viruses, cancer vaccines, and checkpoint blockade inhibitors that have been recently investigated in glioblastoma. Current clinical trials and previous clinical trial findings are discussed, shedding light on novel strategies to overcome various limitations and challenges.", "journal": "Human vaccines & immunotherapeutics", "publication_date": "2022-03-28", "doi": "10.1080/21645515.2022.2055417", "authors": [ "Boyang Yuan", "Guoqing Wang", "Xin Tang", "Aiping Tong", "Liangxue Zhou" ], "keywords": [ "Immunotherapy", "Oncolytic Viruses", "Immunologic Factors", "oncolytic virus", "chimeric antigen receptor (CAR) T cell", "immunotherapy", "Cancer Vaccines", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "39665363", "title": "Machine learning-based prognostic subgrouping of glioblastoma: A multicenter study.", "abstract": "BACKGROUND: Glioblastoma (GBM) is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification. METHODS: We developed a highly reproducible, personalized prognostication, and clinical subgrouping system using machine learning (ML) on routine clinical data, magnetic resonance imaging (MRI), and molecular measures from 2838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, and III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]). RESULTS: The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95% CI: 1.43-1.84, P < .001) and 3.48 (95% CI: 2.94-4.11, P < .001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort. CONCLUSIONS: Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach to personalized patient management and clinical trial stratification in GBM.", "journal": "Neuro-oncology", "publication_date": "2025-05", "doi": "10.1093/neuonc/noae260", "authors": [ "Hamed Akbari", "Spyridon Bakas", "Chiharu Sako", "Anahita Fathi Kazerooni", "Javier Villanueva-Meyer" ], "keywords": [ "mpMRI", "glioblastoma", "Prognosis", "Glioblastoma", "Machine Learning", "Humans", "survival", "Male", "prognostic subgrouping", "Middle Aged", "Female", "Adult", "Follow-Up Studies", "Aged", "Magnetic Resonance Imaging", "Young Adult", "machine learning", "Survival Rate", "Brain Neoplasms" ] }, { "pmid": "33525329", "title": "Reuse of Molecules for Glioblastoma Therapy.", "abstract": "Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12-18 months. New and emerging treatments include the application of a physical device, non-invasive 'tumor treating fields' (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use.", "journal": "Pharmaceuticals (Basel, Switzerland)", "publication_date": "2021-01-28", "doi": "10.3390/ph14020099", "authors": [ "Abigail Koehler", "Aniruddha Karve", "Pankaj Desai", "Jack Arbiser", "David R Plas" ], "keywords": [ "saposin C", "CellCept®", "imipramine blue", "glioblastoma", "Visudyne®", "S6K1 inhibitors", "letrozole", "brain cancer" ] }, { "pmid": "34359621", "title": "Immunotherapy in Glioblastoma: A Clinical Perspective.", "abstract": "Glioblastoma is the most frequent and the most aggressive brain tumor. It is notoriously resistant to current treatments, and the prognosis remains dismal. Immunotherapies have revolutionized the treatment of numerous cancer types and generate great hope for glioblastoma, alas without success until now. In this review, the rationale underlying immune targeting of glioblastoma, as well as the challenges faced when targeting these highly immunosuppressive tumors, are discussed. Innovative immune-targeting strategies including cancer vaccines, oncolytic viruses, checkpoint blockade inhibitors, adoptive cell transfer, and CAR T cells that have been investigated in glioblastoma are reviewed. From a clinical perspective, key clinical trial findings and ongoing trials are discussed for each approach. Finally, limitations, either biological or arising from trial designs are analyzed, and strategies to overcome them are presented. Proof of efficacy for immunotherapy approaches remains to be demonstrated in glioblastoma, but our rapidly expanding understanding of its biology, its immune microenvironment, and the emergence of novel promising combinatorial approaches might allow researchers to finally fulfill the medical need for GBM patients.", "journal": "Cancers", "publication_date": "2021-07-24", "doi": "10.3390/cancers13153721", "authors": [ "Nicolas Desbaillets", "Andreas Felix Hottinger" ], "keywords": [ "CAR T cell", "vaccine", "glioblastoma", "oncolytic virus", "immunotherapy", "checkpoint inhibitor" ] }, { "pmid": "35509452", "title": "Glioblastoma: Pitfalls and Opportunities of Immunotherapeutic Combinations.", "abstract": "Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumour in adults. It has extremely poor prognosis since the current standard of care, comprising of gross total resection and temozolomide (TMZ) chemoradiotherapy, prolongs survival, but does not provide a durable response. To a certain extent, this is due to GBM's heterogeneous, hostile and cold tumour microenvironment (TME) and the unique ability of GBM to overcome the host's immune responses. Therefore, there is an urgent need to develop more effective therapeutic approaches. This review provides critical insights from completed and ongoing clinical studies investigating novel immunotherapy strategies for GBM patients, ranging from the use of immune checkpoint inhibitors in different settings of GBM treatment to novel combinatorial therapies. In particular, we discuss how treatment regimens based on single antigen peptide vaccines evolved into fully personalised, polyvalent cell-based vaccines, CAR-T cell, and viral or gene therapies. Furthermore, the results of the most influential clinical trials and a selection of innovative preclinical studies aimed at activating the immunologically cold GBM microenvironment are reviewed.", "journal": "OncoTargets and therapy", "publication_date": "2022-04-28", "doi": "10.2147/OTT.S215997", "authors": [ "Marcin Niedbała", "Katarzyna Malarz", "Gitanjali Sharma", "Gabriela Kramer-Marek", "Wojciech Kaspera" ], "keywords": [ "viral therapy", "targeted therapy", "CAR-T", "vaccine", "immune checkpoint", "gene therapy", "adoptive cell therapy", "tumour microenvironment", "CAR-NK", "glioblastoma multiforme" ] }, { "pmid": "36825454", "title": "Top advances of the year: Neuro-oncology.", "abstract": "Management of brain tumors has been challenging given the limited therapeutic options and disabling morbidities associated with central nervous system (CNS) dysfunction. This review focuses on recent developments in the field, with an emphasis on clinical management. The growing clinical trials landscape reflects advanced insights into cancer immunology and genomics and the need to address molecular and clinical heterogeneity. Recent phase 3 trials investigating anti-PD-1 immunotherapies, particularly nivolumab, have failed to demonstrate improved survival in glioblastoma, underscoring the need to better understand the complexity of CNS immunologic surveillance. Conversely, targeted therapies have accounted for several US Food and Drug Administration approvals extended to brain tumors, particularly therapies directed to BRAF V600E mutations and TRAK fusions, underscoring a need to routinely screen patients for these rare molecular abnormalities. In primary CNS lymphoma, attention has turned to long-term outcomes of consolidation therapies, and recent studies have highlighted the excellent disease control afforded by high-dose chemotherapy and stem cell transplantation. Meningiomas remain a focus of investigations, with preliminary promising results observed with octreotide combined with mTOR inhibition, and immunotherapy with single-agent pembrolizumab. Finally, proton radiotherapy has emerged as a novel alternative for leptomeningeal metastases from solid tumors, which can now be treated more safely with craniospinal irradiation and monitored by the enumeration of circulating tumor cells in the cerebrospinal fluid as a biomarker. Taken together, these incremental advances have improved outcomes in select brain tumor patient populations, whereas ongoing clinical trials hold the promise of meaningful advances and breakthroughs for larger proportions of patients with brain tumors.", "journal": "Cancer", "publication_date": "2023-02-24", "doi": "10.1002/cncr.34711", "authors": [ "Mary M Barden", "Antonio M Omuro" ], "keywords": [ "leptomeningeal metastasis", "glioma", "primary central nervous system (CNS) lymphoma", "radiotherapy", "Meningeal Neoplasms", "glioblastoma", "meningioma", "immunotherapy", "primary brain neoplasms", "targeted molecular therapy", "Glioblastoma", "Humans", "Meningioma", "Brain Neoplasms" ] }, { "pmid": "36638331", "title": "Key Clinical Principles in the Management of Glioblastoma.", "abstract": "Glioblastoma is the most common and aggressive primary brain tumor in the adult population and leads to considerable morbidity and mortality. It has a dismal prognosis with average survival of 15-18 months, and the current standard-of-care treatment paradigm includes maximal surgical resection and postoperative concurrent chemoradiotherapy and maintenance chemotherapy, with consideration of Tumor Treating Fields. There is a major emphasis to enroll patients onto ongoing clinical trials to further improve treatment outcomes, given the aggressive nature of the disease course and poor patient survival. Recent research efforts have focused on radiotherapy dose intensification, regulation of the tumor microenvironment, and exploration of immunotherapeutic approaches to overcome the barriers to treatment. This review article outlines the current evidence-based management principles as well as reviews recent clinical trial data and ongoing clinical studies evaluating novel therapeutic options.", "journal": "JCO oncology practice", "publication_date": "2023-01-13", "doi": "10.1200/OP.22.00476", "authors": [ "Rupesh Kotecha", "Yazmin Odia", "Atulya A Khosla", "Manmeet S Ahluwalia" ], "keywords": [ "Adult", "Prognosis", "Treatment Outcome", "Chemoradiotherapy", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "38928445", "title": "Recurrent Glioblastoma-Molecular Underpinnings and Evolving Treatment Paradigms.", "abstract": "Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.", "journal": "International journal of molecular sciences", "publication_date": "2024-06-19", "doi": "10.3390/ijms25126733", "authors": [ "Christopher Chang", "Velina S Chavarro", "Jakob V E Gerstl", "Sarah E Blitz", "Lennard Spanehl" ], "keywords": [ "neuro-oncology", "Animals", "recurrent glioblastoma", "neurosurgery", "Glioblastoma", "Tumor Microenvironment", "Humans", "Oncolytic Virotherapy", "Neoplasm Recurrence, Local", "Brain Neoplasms" ] }, { "pmid": "40983311", "title": "New biochemical approaches for the treatment of glioblastoma.", "abstract": "Glioblastoma is a relatively common form of brain tumor for which at present there is no efficient surgical or pharmaceutical treatment. Even with the standard of care consisting of surgery, radiotherapy, plus temozolomide treatment, the median survival time is around 12 months. Recently, several new chemotherapeutic approaches have been developed that target DNA or the circadian clock for treating glioblastoma. Here, after briefly reviewing the standard of care, temozolomide, we summarize the mechanistic bases of these new approaches and their potential for improving treatment of glioblastoma and other brain tumors.", "journal": "The Journal of biological chemistry", "publication_date": "2025-09-20", "doi": "10.1016/j.jbc.2025.110748", "authors": [ "Laura A Lindsey-Boltz", "Aziz Sancar" ], "keywords": [ "Animals", "Glioblastoma", "Humans", "Circadian Clocks", "vorasidenib", "chronotherapy", "EdU", "Temozolomide", "Dacarbazine", "Antineoplastic Agents, Alkylating", "gliocidin", "temozolomide", "M47", "SR9009", "SR9011", "KL-50", "SHP656", "KL001", "5-Ethynyl-2'-deoxyuridine", "Brain Neoplasms" ] }, { "pmid": "33892052", "title": "Extrachromosomal DNA: Redefining the pathogenesis of glioblastoma.", "abstract": "Glioblastoma is an incurable most prevalent primary malignant brain tumor in adults. Surgery followed by radiotherapy with concomitant chemotherapy is the standard of care in patients with glioblastoma. Although, prognosis remains poor with a median survival in the range of 12-15 months. Over the decades of research has identified the gene mutation, angiogenesis, cell signaling for the development novel therapeutics. However, recent understanding on extrachromosomal DNA (ecDNA) put extra-layer of complexity in glioblastoma pathogenesis. These ecDNAs are present in significantly higher copy number in the nucleus of the cancer cells and contains several oncogenes which are instrumental for intra-tumoral genetic heterogeneity, accelerated tumor evolution and therapy resistance. In this review, we will discuss the current understanding on biogenesis, disease progression and potential therapeutic implications of ecDNAs in glioblastoma.", "journal": "Biochimica et biophysica acta. Reviews on cancer", "publication_date": "2021-04-20", "doi": "10.1016/j.bbcan.2021.188551", "authors": [ "Anjali Shiras", "Abir Mondal" ], "keywords": [ "Diagnosis", "Extracellular vesicles", "Animals", "Oncogenes", "EcDNA", "Biomarkers, Tumor", "Therapy resistance", "Brain Neoplasms", "Gene Expression Regulation, Neoplastic", "Prognosis", "Molecular Diagnostic Techniques", "Oncogene amplification", "Genetic Heterogeneity", "Glioblastoma", "Humans", "Predictive Value of Tests", "DNA, Neoplasm", "Signal Transduction" ] }, { "pmid": "36311781", "title": "Advances in immunotherapy for glioblastoma multiforme.", "abstract": "Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.", "journal": "Frontiers in immunology", "publication_date": "2022-10-12", "doi": "10.3389/fimmu.2022.944452", "authors": [ "Ahmad Bakur Mahmoud", "Reham Ajina", "Sarah Aref", "Manar Darwish", "May Alsayb" ], "keywords": [ "glioma", "Immunotherapy", "Immunologic Factors", "oncolytic virotherapy", "Receptors, Chimeric Antigen", "viral vector", "immunotherapy", "Prognosis", "Glioblastoma", "Humans", "CAR-T cells", "checkpoint inhibitors", "Brain Neoplasms", "glioblastoma multiforme" ] }, { "pmid": "33614476", "title": "A Review of Newly Diagnosed Glioblastoma.", "abstract": "Glioblastoma is an aggressive and inevitably recurrent primary intra-axial brain tumor with a dismal prognosis. The current mainstay of treatment involves maximally safe surgical resection followed by radiotherapy over a 6-week period with concomitant temozolomide chemotherapy followed by temozolomide maintenance. This review provides a summary of the epidemiological, clinical, histologic and genetic characteristics of newly diagnosed disease as well as the current standard of care and potential future therapeutic prospects.", "journal": "Frontiers in oncology", "publication_date": "2021-02-05", "doi": "10.3389/fonc.2020.574012", "authors": [ "Bryan Oronsky", "Tony R Reid", "Arnold Oronsky", "Navjot Sandhu", "Susan J Knox" ], "keywords": [ "radiation therapy", "high-grade gliomas", "brain tumors", "glioblastoma", "cancer" ] }, { "pmid": "37984008", "title": "Drivers of heterogeneity in the glioblastoma immune microenvironment.", "abstract": "Glioblastoma is the most common and aggressive primary brain tumor, characterized by a highly complex and heterogeneous tumor immune microenvironment (TIME). In this review, we discuss the impact of tumor-intrinsic and tumor-extrinsic drivers that contribute to heterogeneity in the adult glioblastoma TIME, focusing on four main factors: genetic drivers, sex, age, and standard of care therapy. We describe recent insights into how each of these factors affects key aspects ranging from TIME composition to therapy response, with an emphasis on the cross-talk between tumor and immune cells. Deciphering these local interactions is fundamental to understanding therapy resistance and identifying novel immunomodulatory strategies.", "journal": "Current opinion in cell biology", "publication_date": "2023-11-18", "doi": "10.1016/j.ceb.2023.102279", "authors": [ "Alina Brosque", "Dinorah Friedmann-Morvinski" ], "keywords": [ "Adult", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "34208864", "title": "The Role of NKT Cells in Glioblastoma.", "abstract": "Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms at play in the glioblastoma tumor microenvironment. We propose that Natural Killer T (NKT) cells, which are unconventional T lymphocytes that recognize lipid antigens presented by CD1d molecules, may play a key immunoregulatory role in glioblastoma. For example, evidence suggests that the activation of type I NKT cells can facilitate anti-glioblastoma immune responses. On the other hand, type II NKT cells are known to play an immunosuppressive role in other cancers, as well as to cross-regulate type I NKT cell activity, although their specific role in glioblastoma remains largely unclear. This review provides a summary of our current understanding of NKT cells in the immunoregulation of glioblastoma as well as highlights the involvement of NKT cells in other cancers and central nervous system diseases.", "journal": "Cells", "publication_date": "2021-06-30", "doi": "10.3390/cells10071641", "authors": [ "Emily E S Brettschneider", "Masaki Terabe" ], "keywords": [ "natural killer T cell (NKT)", "glioma", "lipid antigen", "Immunity", "Natural Killer T-Cells", "Lipids", "tumor immunity", "glioblastoma", "Brain", "brain tumor", "Glioblastoma", "Tumor Microenvironment", "Humans" ] }, { "pmid": "34207158", "title": "Targeting CDK9 for the Treatment of Glioblastoma.", "abstract": "Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma.", "journal": "Cancers", "publication_date": "2021-06-18", "doi": "10.3390/cancers13123039", "authors": [ "Alice Ranjan", "Ying Pang", "Madison Butler", "Mythili Merchant", "Olga Kim" ], "keywords": [ "clinical trial", "CDK9 inhibitor", "glioblastoma" ] }, { "pmid": "35078492", "title": "Immunotherapy for glioblastoma: the promise of combination strategies.", "abstract": "Glioblastoma (GBM) treatment has remained almost unchanged for more than 20 years. The current standard of care involves surgical resection (if possible) followed by concomitant radiotherapy and chemotherapy. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. However, mostly due to the high, multifactorial immunosuppression occurring in the microenvironment, the poor knowledge of the neuroimmune system and the presence of the blood-brain barrier, the efficacy of immunotherapy in GBM is still low. Recently, new strategies for GBM treatments have employed immunotherapy combinations and have provided encouraging results in both preclinical and clinical studies. The lessons learned from clinical trials highlight the importance of tackling different arms of immunity. In this review, we aim to summarize the preclinical evidence regarding combination immunotherapy in terms of immune and survival benefits for GBM management. The outcomes of recent studies assessing the combination of different classes of immunotherapeutic agents (e.g., immune checkpoint blockade and vaccines) will be discussed. Finally, future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM.", "journal": "Journal of experimental & clinical cancer research : CR", "publication_date": "2022-01-25", "doi": "10.1186/s13046-022-02251-2", "authors": [ "Mathilde Bausart", "Véronique Préat", "Alessio Malfanti" ], "keywords": [ "Immunotherapy", "Cancer vaccine", "Immune checkpoint blockade", "Immune Checkpoint Inhibitors", "Glioblastoma", "Humans", "Combination immunotherapy", "Brain cancer", "Brain Neoplasms" ] }, { "pmid": "35203636", "title": "Immunotherapeutic Approaches for Glioblastoma Treatment.", "abstract": "Glioblastoma remains a challenging disease to treat, despite well-established standard-of-care treatments, with a median survival consistently of less than 2 years. In this review, we delineate the unique disease-specific challenges for immunotherapies, both brain-related and non-brain-related, which will need to be adequately overcome for the development of effective treatments. We also review current immunotherapy treatments, with a focus on clinical applications, and propose future directions for the field of GBM immunotherapy.", "journal": "Biomedicines", "publication_date": "2022-02-11", "doi": "10.3390/biomedicines10020427", "authors": [ "Nasser K Yaghi", "Mark R Gilbert" ], "keywords": [ "biologic therapy", "glioma", "chemotherapy", "radiotherapy", "GBM", "glioblastoma", "surgery" ] }, { "pmid": "35976319", "title": "Immune-checkpoint inhibitors for glioblastoma: what have we learned?", "abstract": "BACKGROUND: Glioblastoma, the most common malignant primary brain tumor, remains a lethal disease with few therapeutic options. Immunotherapies, particularly immune checkpoint inhibitors (ICPi), have revolutionized cancer treatment, but their role in glioblastoma is uncertain. OBJECTIVE: To review the state of immunotherapies in glioblastoma, with an emphasis on recently published ICPi clinical trials. METHODS: In this editorial/opinion article, we critically review results of the first generation of trials of ipilimumab, nivolumab and pembrolizumab in glioblastoma, as well as future directions. RESULTS: Expression of PD-L1 is frequent in glioblastoma, ranging from 60-70% of patients. Phase 1 studies of nivolumab with and without ipilimumab, as well as pembrolizumab, showed no new safety concerns in brain tumors, and no neurotoxicity. However, randomized phase 3 trials of nivolumab showed no survival improvements over bevacizumab in recurrent glioblastoma; no role in newly diagnosed disease as a replacement for temozolomide in unmethylated MGMT promoter tumors; and no benefit as an addition to temozolomide in methylated MGMT tumors. However, studies examining post treatment tumor samples have shown signs of increased immunologic response, and occasional long lasting radiographic responses have been seen. A small study of pembrolizumab suggested a potential role as a \"neoadjuvant\" treatment in resectable recurrent glioblastoma, while other studies are investigating selection of patients with higher mutational burden and novel agents and combinatorial strategies. CONCLUSION: Despite initial negative trials, immunotherapy remains of high interest in glioblastoma, and many trials are still ongoing. Improving our mechanistic understanding of the immunosuppression and T cell dysfunction induced by both tumor and the CNS microenvironment remains however crucial for the development of successful immunotherapeutic approaches in this disease.", "journal": "Arquivos de neuro-psiquiatria", "publication_date": "2022-05", "doi": "10.1590/0004-282X-ANP-2022-S129", "authors": [ "Antonio Omuro" ], "keywords": [ "Clinical Trials, Phase III as Topic", "Immunotherapy", "Randomized Controlled Trials as Topic", "Ipilimumab", "Tumor Microenvironment", "Immune Checkpoint Inhibitors", "Glioblastoma", "Nivolumab", "Humans", "Neoplasm Recurrence, Local", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "35900527", "title": "An overview of targets and therapies for glioblastoma multiforme.", "abstract": "Glioblastoma multiforme (GBM) affects individuals above 65 years of age and has low median survival rate. Due to limited treatment options, lack of effective diagnosis, and palliative care, there is an urgent need to develop new therapeutic strategies to combat GBM. This review provides an overview of the current clinical trial scenario with a special focus on new targets, repurposed drugs, and technologies in the field of GBM. The use of technological advances and artificial intelligence in diagnosis and imaging is also discussed. In addition, this review also highlights the need to design a dynamic palliative care strategy for end-of-life management of patients with GBM.", "journal": "Journal of cancer research and therapeutics", "publication_date": "2022", "doi": "10.4103/jcrt.jcrt_1324_21", "authors": [ "Gayathri Chandrasekar", "Vinay Scheel Bansal", "Manas Panigrahi", "Satish S Kitambi" ], "keywords": [ "Palliative Care", "glioma", "Artificial Intelligence", "drug", "Survival Rate", "treatment", "Cancer", "glioblastoma", "care", "Glioblastoma", "Humans", "Brain Neoplasms" ] }, { "pmid": "37256535", "title": "Novel Immunotherapeutic Approaches for the Treatment of Glioblastoma.", "abstract": "Glioblastoma is highly aggressive and remains difficult to treat despite being the most common malignant primary brain tumor in adults. Current standard-of-care treatment calls for maximum resection of the tumor mass followed by concurrent chemotherapy and radiotherapy and further adjuvant chemotherapy if necessary. Despite this regimen, prognosis remains grim. Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include: a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood-brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations. In this review, we present different classes of immunotherapy targeting glioblastoma, their most recent results, and potential future directions.", "journal": "BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy", "publication_date": "2023-05-31", "doi": "10.1007/s40259-023-00598-2", "authors": [ "Saïf Eddine Zaidi", "Eliese Moelker", "Kirit Singh", "Aditya Mohan", "Miguel A Salgado" ], "keywords": [ "Blood-Brain Barrier", "Immunotherapy", "Adult", "Immunosuppressive Agents", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "37994751", "title": "Omics sciences and precision medicine in glioblastoma.", "abstract": "Glioblastoma is a highly aggressive and malignant type of brain cancer with a poor prognosis, despite current treatment options of surgery, radiation therapy, and chemotherapy. These treatments have limitations due to the aggressive nature of the cancer and the difficulty in completely removing the tumor without damaging healthy brain tissue. Personalized medicine, using genomic profiling to tailor treatment to the patient's specific tumor, and immunotherapy have shown promise in clinical trials. The blood-brain barrier also poses a challenge in delivering treatments to the brain, and researchers are exploring various approaches to bypass it. More effective, personalized treatment approaches are needed to improve outcomes for glioblastoma patients. This tumor is studied using genomics, transcriptomics, and proteomics techniques, to better understand its underlying molecular mechanisms. Recent studies have used these techniques to identify potential therapeutic targets, molecular subtypes, and heterogeneity of tumor cells. Advancements in omics sciences have improved our understanding of glioblastoma biology, and precision medicine approaches have impli-cations for more accurate diagnoses, improved treatment outcomes, and personalized preventive care. Precision medicine can match patients with drugs that target specific genetic mutations, improve clinical trials, and identify individuals at higher risk for certain diseases. Precision medicine, which involves customizing medical treatment based on an individual's genetic makeup, lifestyle, and environmental factors, has shown promise in improving treatment outcomes for glioblastoma patients. Identifying biomarkers is essential for patient stratification and treatment selection in precision medicine approaches for glioblastoma, and several biomarkers have shown promise in predicting patient response to treatment. Targeted therapies are a key component of precision medicine approaches in glioblastoma, but there is still a need to improve their effectiveness. Technical challenges, such as sample quality and availability, and challenges in analyzing and interpreting large amounts of data remain significant obstacles in omics sciences and precision medicine for glioblastoma. The clinical implementation of precision medicine in glioblastoma treatment faces challenges related to patient selection, drug development, and clinical trial design, as well as ethical and legal considerations related to patient privacy, informed consent, and access to expensive treatments.", "journal": "La Clinica terapeutica", "publication_date": "2023", "doi": "10.7417/CT.2023.2474", "authors": [ "C Micheletti", "G Bonetti", "G Madeo", "M Gadler", "S Benedetti" ], "keywords": [ "therapy", "diagnosis", "Precision Medicine", "genomics", "precision medicine", "metabolomics", "Glioblastoma", "omics sciences", "Humans", "proteomics", "Biomarkers", "Proteomics", "Brain Neoplasms" ] }, { "pmid": "39195222", "title": "Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance.", "abstract": "Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.", "journal": "Cells", "publication_date": "2024-08-11", "doi": "10.3390/cells13161332", "authors": [ "Young Keun Hwang", "Dong-Hun Lee", "Eun Chae Lee", "Jae Sang Oh" ], "keywords": [ "Animals", "chemoresistance", "autophagy", "glioblastoma", "temozolomide", "Signal Transduction", "Autophagy", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "40705602", "title": "Cell-of-origin-specific behavioral deficits in oligodendrocyte-derived glioblastoma.", "abstract": "Glioblastoma (GBM) remains the most lethal primary brain tumor, persisting despite multimodal standard-of-care therapy. One of the major challenges for effective treatment of these tumors is their high heterogeneity, which stems, in part, from differences in the cell of origin. Using a CNP-Cre transgenic mouse model, this study investigates the role of differentiated oligodendrocytes as a candidate cell of origin for GBM. We show that these cells can give rise to GBM tumors when targeted with Cre-inducible oncogenic lentiviral vectors. Notably, in mice these oligodendrocyte-derived GBM tumors lead to early-onset motor deficits that are not observed in neuron-derived tumors. In addition, these tumors exhibit a distinct transcriptional profile involving altered expression of myelin-related genes, emphasizing the impact of the cell of origin on both molecular and behavioral phenotypes of GBM. We believe that a deeper understanding of the identity of the cell of origin may contribute to uncovering new mechanisms and therapeutic vulnerabilities in GBM.", "journal": "Cell reports", "publication_date": "2025-07-23", "doi": "10.1016/j.celrep.2025.116043", "authors": [ "Divsha Sher", "Ignacio Mastandrea", "Alina Brosque", "Gilad Levy", "Itamar Ironi" ], "keywords": [ "cell of origin", "Animals", "myelin", "glioblastoma", "Glioblastoma", "Humans", "Disease Models, Animal", "Oligodendroglia", "motor deficits", "oligodendrocytes", "Mice, Transgenic", "transcriptomic profile", "in vivo models", "Mice", "CNP", "oncogenic lentivirus", "CP: Cancer", "brain tumor", "Cell Differentiation", "Brain Neoplasms" ] }, { "pmid": "40682424", "title": "Status and Prospects of Glioblastoma Multiforme Treatments.", "abstract": "Glioblastoma multiforme (GBM) is the most aggressive and common primary brain cancer in adults. Its standard-of-care therapy encompasses surgical resection, radiotherapy, and chemotherapy. Although this combination therapy somewhat extends patient survival, its efficacy remains limited, and the recurrence rate remains high. In recent years, novel therapeutic approaches for the treatment of GBM have emerged: (i) tumor-treating fields delivering nonionizing low-intensity alternating electric fields to disrupt mitosis; (ii) molecular targeted therapies that inhibit specific gene mutations or signaling pathways; (iii) immunotherapy that activates the patient's own immune system to fight this cancer; (iv) proton therapy, which, with its precise radiation dose distribution, minimizes damage to the normal brain parenchyma surrounding the GBM; (v) oncolytic virus therapy to selectively infect and lyse GBM cells; (vi) the use of nanoparticle carriers for targeted drug delivery to increase therapeutic efficacy and reduce side effects; (vii) phototherapy; and (viii) sonodynamic therapy. The purpose of this narrative is to review both standard-of-care and novel contemporary approaches to this devastating cancer. In the future, with further advancements in multiomics technologies, artificial intelligence, and novel biomaterials, GBM treatment should move toward more personalized, precise, and comprehensive approaches, offering patients more effective treatment options.", "journal": "Journal of neurochemistry", "publication_date": "2025-07", "doi": "10.1111/jnc.70158", "authors": [ "Xue Yang", "Shibing Wang", "Vedrana Montana", "Xiangmin Tong", "Vladimir Parpura" ], "keywords": [ "oncolytic viruses", "Molecular Targeted Therapy", "molecular targeting", "Animals", "Immunotherapy", "phototherapy", "Combined Modality Therapy", "GBM", "personalized medicine", "tumor‐treating fields", "immunotherapy", "sonodynamic therapy", "nanoparticle carriers", "Glioblastoma", "Humans", "Oncolytic Virotherapy", "standard‐of‐care", "Brain Neoplasms" ] }, { "pmid": "34054867", "title": "Immunotherapy for Glioblastoma: Current Progress and Challenges.", "abstract": "Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.", "journal": "Frontiers in immunology", "publication_date": "2021-05-13", "doi": "10.3389/fimmu.2021.676301", "authors": [ "Miranda W Yu", "Daniela F Quail" ], "keywords": [ "Animals", "Tumor-Associated Macrophages", "glioblastoma", "Immune Checkpoint Inhibitors", "Treatment Outcome", "Cancer Vaccines", "Glioblastoma", "immunotherapy", "Humans", "resistance to therapy", "Disease Models, Animal", "Immunotherapy, Adoptive", "Molecular Targeted Therapy", "tumor microenvironment", "Vaccination", "Mice", "Tumor Microenvironment", "Brain Neoplasms", "brain cancer" ] }, { "pmid": "39192069", "title": "Glioblastoma in the real-world setting: patterns of care and outcome in the Austrian population.", "abstract": "PURPOSE: We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria. PATIENTS AND METHODS: In this nation-wide cooperative project, all Austrian glioblastoma patients newly diagnosed between 2014 and 2018 and registered in the ABTR-SANOnet database were included. Histological typing used criteria of the WHO classification of CNS tumors, 4th edition 2016. Patterns of care were assessed, and all patients were followed until the end of 2019. RESULTS: 1,420 adult glioblastoma cases were identified. 813 (57.3%) patients were male and 607 (42.7%) female. Median age at diagnosis was 64 years (range: 18-88). Median overall survival (OS) was 11.6 months in the total cohort and 10.9 months in patients with proven IDH-wildtype. Median OS in the patient group ≤ 65 years receiving postoperative standard of care therapy was 16.1 months. In the patient group > 65 years with postoperative therapy, median OS was 11.2 months. Follow-up ≥ 5 years identified 13/264 (4.9%) long-term survivors. Brain tumor surgery frequently was assisted by 5-aminolevulinic acid (5-ALA) fluorescence (up to 55%). Postoperative treatment was initiated around one month after surgery (median: 31 days) following standardized protocols in 1,041/1,420 (73.3%) cases. In 830 patients (58.5%), concomitant radiochemotherapy was started according to the established standard of care. Treatment in case of progressive disease was considerably variable. 170/1,420 patients (12.0%) underwent a second surgical procedure, 467 (33.0%) received systemic treatment after progression, and 173 (12.2%) were re-irradiated. CONCLUSION: Our data illustrate and confirm nation-wide translation of effective standard of care to Austrian glioblastoma patients in the recent past. In the case of progressive disease, highly variable therapeutic approaches were used, most frequently accompanied by anti-angiogenic therapy. Long-term survival was observed in a minor proportion of mostly younger patients who typically had gross total tumor resection, a favorable postoperative ECOG score, and standard of care therapy.", "journal": "Journal of neuro-oncology", "publication_date": "2024-08-27", "doi": "10.1007/s11060-024-04808-x", "authors": [ "Andreas Hainfellner", "Martin Borkovec", "Lukas Seebrecht", "Magdalena Neuhauser", "Thomas Roetzer-Pejrimovsky" ], "keywords": [ "Prognosis", "Treatment Outcome", "Austria", "Glioblastoma", "Humans", "Adolescent", "Male", "Retrospective Studies", "Middle Aged", "Registry", "Female", "Adult", "Follow-Up Studies", "Aged", "Outcome", "Young Adult", "Survival Rate", "Combined Modality Therapy", "Aged, 80 and over", "Brain Neoplasms" ] }, { "pmid": "40996961", "title": "CDK12 regulates cellular metabolism to promote glioblastoma growth.", "abstract": "Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patient-derived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³C-glutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12/GSK3β/PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.", "journal": "JCI insight", "publication_date": "2025-09-25", "doi": "10.1172/jci.insight.190780", "authors": [ "Jeong-Yeon Mun", "Chang Shu", "Qiuqiang Gao", "Zhe Zhu", "Hasan O Akman" ], "keywords": [ "Mitochondria", "Metabolism", "Animals", "Oncogenes", "Oncology", "Mice", "Cyclin-Dependent Kinases", "Glycogen Synthase Kinase 3 beta", "Brain cancer", "Cell Proliferation", "Glioblastoma", "Female", "Humans", "Apoptosis", "Xenograft Model Antitumor Assays", "Cell Line, Tumor", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "40386781", "title": "An update on the clinical trial research of immunotherapy for glioblastoma.", "abstract": "Glioblastoma multiforme (GBM) is a common primary malignant brain tumor in adults, characterized by a high rate of recurrence and mortality. The median overall survival is less than 2 years with the current standard therapy. As immunotherapy has begun to show promising results in solid tumors such as non-small cell lung cancer and melanoma in recent years, immnunotherapy for patients with glioblastoma is also in full swing, which is mainly consisted of immune checkpoint inhibitors, cancer vaccines, chimeric antigen receptor T-cell and oncolytic viral therapy. However, the application of immunotherapy in glioblastoma is severely hampered by cognitive impairment of intracerebral lymphatic system, the existence of blood-brain barrier, highly immunosuppressive tumor microenvironment and GBM's intrinsic features, including low tumor mutation burden and high heterogeneity. This review systematically evaluates recently published clinical trial outcomes of GBM immunotherapy, critically analyses both the progress and limitations of these trials, thoroughly examines current barriers to effective immunotherapy, and highlights promising preclinical studies that may guide future therapeutic development.", "journal": "Frontiers in immunology", "publication_date": "2025-05-02", "doi": "10.3389/fimmu.2025.1582296", "authors": [ "Yichen Zhou", "Fanxing Shi", "Junyu Zhu", "Yi Yuan" ], "keywords": [ "Animals", "CAR-T", "glioblastoma", "Immune Checkpoint Inhibitors", "Treatment Outcome", "Cancer Vaccines", "Glioblastoma", "Humans", "Oncolytic Virotherapy", "oncolytic virus therapy", "Immunotherapy", "Clinical Trials as Topic", "DC vaccines", "CTLA-4 inhibitors", "immune checkpoint inhibitors", "tumor vaccine", "Tumor Microenvironment", "PD-1 inhibitors", "Brain Neoplasms" ] }, { "pmid": "40775789", "title": "Glioblastoma metabolomics: uncovering biomarkers for diagnosis, prognosis and targeted therapy.", "abstract": "Glioblastoma (GBM) is characterized by rapid growth, high molecular heterogeneity, and invasiveness. Specific aggressive factors are represented by MGMT promoter methylation, and IDH mutation status. Current standard-of-care for GBM includes surgical resection, followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. However, patients almost invariably succumb due to therapy resistance and disease recurrences. Therefore, novel therapies for GBM are urgently needed to improve patient survival, necessitating the identification of new diagnostic and prognostic biomarkers, as well as therapeutic targets.In this context, \"omics\" technologies, such as metabolomics and lipidomics, can generate vast amounts of data useful to elucidate the complex molecular mechanisms driving this disease, and discover potential novel biomarkers and therapeutic targets. Our review aims to highlight the current literature on the metabolomics studies conducted on GBM biological matrices, such as in vitro and in vivo models, tissues and biofluids, including plasma, saliva and cerebrospinal fluid.From the data reported here, it appears that metabolic reprogramming in GBM is characterized by dysregulation in multiple pathways, particularly glycolysis (Warburg effect), amino acid metabolism, and the urea cycle, and the metabolic changes disclose promising tumor targets.", "journal": "Journal of experimental & clinical cancer research : CR", "publication_date": "2025-08-07", "doi": "10.1186/s13046-025-03497-2", "authors": [ "Susan Costantini", "Elena Di Gennaro", "Giulia Fanelli", "Palmina Bagnara", "Chiara Argenziano" ], "keywords": [ "Molecular Targeted Therapy", "Animals", "Biomarkers, Tumor", "Magnetic resonance", "Prognosis", "Metabolomics", "Glioblastoma", "Mass spectrometry", "Humans", "Brain Neoplasms" ] }, { "pmid": "37275361", "title": "Barriers to overcoming immunotherapy resistance in glioblastoma.", "abstract": "Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, known for its poor prognosis and high recurrence rate. Current standard of care includes surgical resection followed by combined radiotherapy and chemotherapy. Although immunotherapies have yielded promising results in hematological malignancies, their successful application in GBM remains limited due to a host of immunosuppressive factors unique to GBM. As a result of these roadblocks, research efforts have focused on utilizing combinatorial immunotherapies that target networks of immune processes in GBM with promising results in both preclinical and clinical trials, although limitations in overcoming the immunosuppressive factors within GBM remain. In this review, we aim to discuss the intrinsic and adaptive immune resistance unique to GBM and to summarize the current evidence and outcomes of engineered and non-engineered treatments targeted at overcoming GBM resistance to immunotherapy. Additionally, we aim to highlight the most promising strategies of targeted GBM immunotherapy combinatorial treatments and the insights that may directly improve the current patient prognosis and clinical care.", "journal": "Frontiers in medicine", "publication_date": "2023-05-18", "doi": "10.3389/fmed.2023.1175507", "authors": [ "Julia S Gillette", "Elaina J Wang", "Richard S Dowd", "Steven A Toms" ], "keywords": [ "vaccine", "chimeric antigen receptor (CAR) T cells", "gliobalstoma", "virotherapy", "immunotherapy", "checkpoint inhibitors", "resistance" ] }, { "pmid": "37121239", "title": "The complexities underlying epilepsy in people with glioblastoma.", "abstract": "Seizures are among the most common clinical signs in people with glioblastoma. Advances over the past 5 years, including new clinical trial data, have increased the understanding of why some individuals with glioblastoma are susceptible to seizures, how seizures manifest clinically, and what implications seizures have for patient management. The pathophysiology of epilepsy in people with glioblastoma relates to a combination of intrinsic epileptogenicity of tumour tissue, alterations in the tumour and peritumoural microenvironment, and the physical and functional disturbance of adjacent brain structures. Successful management of epilepsy in people with glioblastoma remains challenging; factors such as drug-drug interactions between cancer therapies and antiseizure medications, and medication side-effects, can affect seizure outcomes and quality of life. Advances in novel therapies provide some promise for people with glioblastoma; however, the effects of these therapies on seizures are yet to be fully determined. Looking forward, insights into electrical activity as a driver of tumour cell growth and the intrinsic hyperexcitability of tumour tissue might represent useful targets for treatment and disease modification. There is a pressing need for large randomised clinical trials in this field.", "journal": "The Lancet. Neurology", "publication_date": "2023-04-27", "doi": "10.1016/S1474-4422(23)00031-5", "authors": [ "Elisaveta Sokolov", "Jorg Dietrich", "Andrew J Cole" ], "keywords": [ "Epilepsies, Partial", "Anticonvulsants", "Quality of Life", "Epilepsy", "Epilepsy, Generalized", "Carbamazepine", "Glioblastoma", "Tumor Microenvironment", "Humans", "Seizures" ] }, { "pmid": "35150865", "title": "Checkpoint: Inspecting the barriers in glioblastoma immunotherapies.", "abstract": "Despite an aggressive standard of care involving radiation therapy, temozolomide-based chemotherapy, and surgical resection, glioblastoma multiforme (GBM) continues to exhibit very high recurrence and mortality rates partly due to the highly plastic and heterogenous nature of the tumor. In recent years, activation of the immune system has emerged as a promising strategy in cancer therapies. However, despite recent successes in other fields, immunotherapeutic approaches continue to encounter challenges in GBM. In this review, we first discuss immunotherapies targeting the most well-studied immune checkpoint proteins, CTLA-4 and PD-1, followed by discussions on therapies targeting immune-stimulatory molecules and secreted metabolic enzymes. Finally, we address the major challenges with immunotherapy in GBM and the potential for combination and neoadjuvant immunotherapies to tip the scales in the fight against glioblastoma.", "journal": "Seminars in cancer biology", "publication_date": "2022-02-10", "doi": "10.1016/j.semcancer.2022.02.012", "authors": [ "Isabelle Preddy", "Khizar Nandoliya", "Jason Miska", "Atique U Ahmed" ], "keywords": [ "Immunotherapy", "Temozolomide", "Checkpoint proteins", "Glioblastoma", "Neoadjuvant Therapy", "Humans", "Immunotherpay", "Biological Transport" ] }, { "pmid": "38899374", "title": "Current status of precision oncology in adult glioblastoma.", "abstract": "The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E-mutated GBM benefit from BRAF/MEK-inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (< 10%) of targeted treatments. Efficacy was observed in one-third and currently appears to be limited to BRAF-, VEGFR-, and mTOR-directed treatments. Advancing precision oncology for GBM requires consideration of pathways instead of single alterations, new trial concepts enabling rapid and adaptive drug evaluation, a focus on drugs with sufficient bioavailability in the CNS, and the extension of target discovery and validation to the tumor microenvironment, tumor cell networks, and their interaction with immune cells and neurons.", "journal": "Molecular oncology", "publication_date": "2024-06-20", "doi": "10.1002/1878-0261.13678", "authors": [ "Johannes Weller", "Anna-Laura Potthoff", "Thomas Zeyen", "Christina Schaub", "Cathrina Duffy" ], "keywords": [ "Molecular Targeted Therapy", "molecular profiling", "Medical Oncology", "Adult", "Precision Medicine", "targeted treatment", "glioblastoma", "precision oncology", "personalized medicine", "Glioblastoma", "Humans", "biomarker", "Brain Neoplasms" ] }, { "pmid": "37371674", "title": "Personalized Treatment of Glioblastoma: Current State and Future Perspective.", "abstract": "Glioblastoma (GBM) is the most aggressive glial tumor of the central nervous system. Despite intense scientific efforts, patients diagnosed with GBM and treated with the current standard of care have a median survival of only 15 months. Patients are initially treated by a neurosurgeon with the goal of maximal safe resection of the tumor. Obtaining tissue samples during surgery is indispensable for the diagnosis of GBM. Technological improvements, such as navigation systems and intraoperative monitoring, significantly advanced the possibility of safe gross tumor resection. Usually within six weeks after the surgery, concomitant radiotherapy and chemotherapy with temozolomide are initiated. However, current radiotherapy regimens are based on population-level studies and could also be improved. Implementing artificial intelligence in radiotherapy planning might be used to individualize treatment plans. Furthermore, detailed genetic and molecular markers of the tumor could provide patient-tailored immunochemotherapy. In this article, we review current standard of care and possibilities of personalizing these treatments. Additionally, we discuss novel individualized therapeutic options with encouraging results. Due to inherent heterogeneity of GBM, applying patient-tailored treatment could significantly prolong survival of these patients.", "journal": "Biomedicines", "publication_date": "2023-05-30", "doi": "10.3390/biomedicines11061579", "authors": [ "Alen Rončević", "Nenad Koruga", "Anamarija Soldo Koruga", "Robert Rončević", "Tatjana Rotim" ], "keywords": [ "chemotherapy", "neurosurgery", "radiotherapy", "glioblastoma", "immunotherapy" ] }, { "pmid": "34570451", "title": "The Challenges and Future of Immunotherapy for Gliomas.", "abstract": "Gliomas and glioblastoma comprise the majority of brain malignancies and are difficult to treat despite standard of care and advances in immunotherapy. The challenges of controlling glioma growth and recurrence involve the uniquely immunosuppressive tumor microenvironment and systemic blunting of immune responses. In addition to highlighting key features of glioma and glioblastoma composition and immunogenicity, this review presents several future directions for immunotherapy, such as vaccines and synergistic combination treatment regimens, to better combat these tumors.", "journal": "Cancer journal (Sudbury, Mass.)", "publication_date": "Unknown", "doi": "10.1097/PPO.0000000000000544", "authors": [ "Adela Wu", "Michael Lim" ], "keywords": [ "Immunotherapy", "Glioblastoma", "Tumor Microenvironment", "Humans", "Neoplasm Recurrence, Local", "Glioma", "Brain Neoplasms" ] }, { "pmid": "37215957", "title": "Convection-enhanced delivery of immunomodulatory therapy for high-grade glioma.", "abstract": "The prognosis for glioblastoma has remained poor despite multimodal standard of care treatment, including temozolomide, radiation, and surgical resection. Further, the addition of immunotherapies, while promising in a number of other solid tumors, has overwhelmingly failed in the treatment of gliomas, in part due to the immunosuppressive microenvironment and poor drug penetrance to the brain. Local delivery of immunomodulatory therapies circumvents some of these challenges and has led to long-term remission in select patients. Many of these approaches utilize convection-enhanced delivery (CED) for immunological drug delivery, allowing high doses to be delivered directly to the brain parenchyma, avoiding systemic toxicity. Here, we review the literature encompassing immunotherapies delivered via CED-from preclinical model systems to clinical trials-and explore how their unique combination elicits an antitumor response by the immune system, decreases toxicity, and improves survival among select high-grade glioma patients.", "journal": "Neuro-oncology advances", "publication_date": "2023-04-21", "doi": "10.1093/noajnl/vdad044", "authors": [ "Colin P Sperring", "Michael G Argenziano", "William M Savage", "Damian E Teasley", "Pavan S Upadhyayula" ], "keywords": [ "immunotherapy", "glioma", "convection-enhanced delivery", "drug delivery" ] }, { "pmid": "36010891", "title": "Challenges in Glioblastoma Radiomics and the Path to Clinical Implementation.", "abstract": "Radiomics is a field of medical imaging analysis that focuses on the extraction of many quantitative imaging features related to shape, intensity and texture. These features are incorporated into models designed to predict important clinical or biological endpoints for patients. Attention for radiomics research has recently grown dramatically due to the increased use of imaging and the availability of large, publicly available imaging datasets. Glioblastoma multiforme (GBM) patients stand to benefit from this emerging research field as radiomics has the potential to assess the biological heterogeneity of the tumour, which contributes significantly to the inefficacy of current standard of care therapy. Radiomics models still require further development before they are implemented clinically in GBM patient management. Challenges relating to the standardisation of the radiomics process and the validation of radiomic models impede the progress of research towards clinical implementation. In this manuscript, we review the current state of radiomics in GBM, and we highlight the barriers to clinical implementation and discuss future validation studies needed to advance radiomics models towards clinical application.", "journal": "Cancers", "publication_date": "2022-08-12", "doi": "10.3390/cancers14163897", "authors": [ "Philip Martin", "Lois Holloway", "Peter Metcalfe", "Eng-Siew Koh", "Caterina Brighi" ], "keywords": [ "machine learning", "radiomics", "MRI", "Glioblastoma", "biomarker" ] }, { "pmid": "40037502", "title": "Advancing glioblastoma therapy: Learning from the past and innovations for the future.", "abstract": "Marred by a median survival of only around 12-15 months coupled with poor prognosis and effective therapeutic deprived drug armory, treatment/management of glioblastoma has proved to be a daunting task. Surgical resection, flanked by radiotherapy and chemotherapy with temozolomide, stands as the standard of care; however, this trimodal therapy often manifests limited efficacy due to the heterogeneous and highly infiltrative nature of GBM cells. In addition, the existence of the blood-brain barrier, tumor microenvironment, and the immunosuppressive nature of GBM, along with the encountered resistance of GBM cells towards conventional therapy, also hinders the therapeutic applications of chemotherapeutics in GBM. This review presents key insights into the molecular pathology of GBM, including genetic mutations, signaling pathways, and tumor microenvironment characteristics. Recent innovations such as immunotherapy, oncolytic viral therapies, vaccines, nanotechnology, electric field, and cancer neuroscience, as well as their clinical progress, have been covered. In addition, this compilation also encompasses a discussion on the role of personalized medicine in tailoring treatments based on individual tumor profiles, an approach that is gradually shifting the paradigm in GBM management. Endowed with the learnings imbibed from past failures coupled with the zeal to embrace novel/multidisciplinary approaches, researchers appear to be on the right track to pinpoint more effective and durable solutions in the context of GBM treatment.", "journal": "Cancer letters", "publication_date": "2025-03-02", "doi": "10.1016/j.canlet.2025.217601", "authors": [ "Mandeep Rana", "Ke-Chi Liou", "Amandeep Thakur", "Kunal Nepali", "Jing-Ping Liou" ], "keywords": [ "Metabolism", "Animals", "Immunotherapy", "Precision Medicine", "Neurons", "Tumor microenvironment", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "38546941", "title": "Novel Clinical Trials and Approaches in the Management of Glioblastoma.", "abstract": "PURPOSE OF REVIEW: The purpose of this review is to discuss a wide variety of novel therapies recently studied or actively undergoing study in patients with glioblastoma. This review also discusses current and future strategies for improving clinical trial design in patients with glioblastoma to maximize efficacy in discovering effective treatments. RECENT FINDINGS: Over the years, there has been significant expansion in therapy modalities studied in patients with glioblastoma. These therapies include, but are not limited to, targeted molecular therapies, DNA repair pathway targeted therapies, immunotherapies, vaccine therapies, and surgically targeted radiotherapies. Glioblastoma is the most common malignant primary brain tumor in adults and unfortunately remains with poor overall survival following the current standard of care. Given the dismal prognosis, significant clinical and research efforts are ongoing with the goal of improving patient outcomes and enhancing quality and quantity of life utilizing a wide variety of novel therapies.", "journal": "Current oncology reports", "publication_date": "2024-03-28", "doi": "10.1007/s11912-024-01519-4", "authors": [ "Allison R Valerius", "Lauren M Webb", "Ugur Sener" ], "keywords": [ "Molecular Targeted Therapy", "Immunotherapy", "CNS tumors", "Clinical Trials as Topic", "Radiotherapy", "Targeted molecular therapy", "High-grade glioma", "Review of therapy", "Cancer Vaccines", "Glioblastoma", "Humans", "Chemotherapy", "Brain Neoplasms" ] }, { "pmid": "39599889", "title": "Oncolytic Virotherapies and Adjuvant Gut Microbiome Therapeutics to Enhance Efficacy Against Malignant Gliomas.", "abstract": "Glioblastoma (GBM) is the most prevalent malignant brain tumor. Current standard-of-care treatments offer limited benefits for patient survival. Virotherapy is emerging as a novel strategy to use oncolytic viruses (OVs) for the treatment of GBM. These engineered and non-engineered viruses infect and lyse cancer cells, causing tumor destruction without harming healthy cells. Recent advances in genetic modifications to OVs have helped improve their targeting capabilities and introduce therapeutic genes, broadening the therapeutic window and minimizing potential side effects. The efficacy of oncolytic virotherapy can be enhanced by combining it with other treatments such as immunotherapy, chemotherapy, or radiation. Recent studies suggest that manipulating the gut microbiome to enhance immune responses helps improve the therapeutic efficacy of the OVs. This narrative review intends to explore OVs and their role against solid tumors, especially GBM while emphasizing the latest technologies used to enhance and improve its therapeutic and clinical responses.", "journal": "Viruses", "publication_date": "2024-11-14", "doi": "10.3390/v16111775", "authors": [ "Natalie M Meléndez-Vázquez", "Candelaria Gomez-Manzano", "Filipa Godoy-Vitorino" ], "keywords": [ "gut microbiome", "Animals", "Immunotherapy", "Oncolytic Viruses", "therapeutic efficacy", "combinatory therapies", "Combined Modality Therapy", "glioblastoma", "viroimmunotherapy", "Gastrointestinal Microbiome", "Glioblastoma", "Humans", "Oncolytic Virotherapy", "Glioma", "Brain Neoplasms" ] }, { "pmid": "38672496", "title": "Mechanism of Notch Signaling Pathway in Malignant Progression of Glioblastoma and Targeted Therapy.", "abstract": "Glioblastoma multiforme (GBM) is the most aggressive form of glioma and the most common primary tumor of the central nervous system. Despite significant advances in clinical management strategies and diagnostic techniques for GBM in recent years, it remains a fatal disease. The current standard of care includes surgery, radiation, and chemotherapy, but the five-year survival rate for patients is less than 5%. The search for a more precise diagnosis and earlier intervention remains a critical and urgent challenge in clinical practice. The Notch signaling pathway is a critical signaling system that has been extensively studied in the malignant progression of glioblastoma. This highly conserved signaling cascade is central to a variety of biological processes, including growth, proliferation, self-renewal, migration, apoptosis, and metabolism. In GBM, accumulating data suggest that the Notch signaling pathway is hyperactive and contributes to GBM initiation, progression, and treatment resistance. This review summarizes the biological functions and molecular mechanisms of the Notch signaling pathway in GBM, as well as some clinical advances targeting the Notch signaling pathway in cancer and glioblastoma, highlighting its potential as a focus for novel therapeutic strategies.", "journal": "Biomolecules", "publication_date": "2024-04-15", "doi": "10.3390/biom14040480", "authors": [ "Shenghao Wang", "Sikuan Gu", "Junfan Chen", "Zhiqiang Yuan", "Ping Liang" ], "keywords": [ "Molecular Targeted Therapy", "Animals", "molecular mechanisms", "biological functions", "Receptors, Notch", "glioblastoma", "Notch", "Disease Progression", "Glioblastoma", "Humans", "clinical", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "37568734", "title": "Systematic Review of Photodynamic Therapy in Gliomas.", "abstract": "Over the last 20 years, gliomas have made up over 89% of malignant CNS tumor cases in the American population (NIH SEER). Within this, glioblastoma is the most common subtype, comprising 57% of all glioma cases. Being highly aggressive, this deadly disease is known for its high genetic and phenotypic heterogeneity, rendering a complicated disease course. The current standard of care consists of maximally safe tumor resection concurrent with chemoradiotherapy. However, despite advances in technology and therapeutic modalities, rates of disease recurrence are still high and survivability remains low. Given the delicate nature of the tumor location, remaining margins following resection often initiate disease recurrence. Photodynamic therapy (PDT) is a therapeutic modality that, following the administration of a non-toxic photosensitizer, induces tumor-specific anti-cancer effects after localized, wavelength-specific illumination. Its effect against malignant glioma has been studied extensively over the last 30 years, in pre-clinical and clinical trials. Here, we provide a comprehensive review of the three generations of photosensitizers alongside their mechanisms of action, limitations, and future directions.", "journal": "Cancers", "publication_date": "2023-08-01", "doi": "10.3390/cancers15153918", "authors": [ "Tiffaney Hsia", "Julia L Small", "Anudeep Yekula", "Syeda M Batool", "Ana K Escobedo" ], "keywords": [ "photosensitizer", "photomedicine", "glioblastoma", "photodynamic therapy" ] }, { "pmid": "33227487", "title": "Biocompatible copolymer formulations to treat glioblastoma multiforme.", "abstract": "The treatment for glioblastoma multiforme (GBM) has not changed for more than 20 years while the prognosis for the patients is still poor and most of them survive less than 1 year after diagnosis. The standard of care for GBM is comprised of surgical resection followed by radiotherapy and oral chemotherapy with temozolomide. The placement of carmustine wafers in the brain after tumour removal is added in cases of recurrent glioma. Significant research is underway to improve the GBM therapy outcome and patient quality of life. Biomaterials are in the front line of the research focus for new treatment options. Specially, biocompatible polymers have been proposed in hydrogel-based formulations aiming at injectable and localized therapies. These formulations can comprise many different pharmacological agents such as chemotherapeutic drugs, nanoparticles, cells, nucleic acids, and diagnostic agents. In this manuscript, we review the most recent formulations developed and tested both in vitro and in vivo using different types of hydrogels. Firstly, we describe three common types of thermo-responsive polymers addressing the advantages and drawbacks of their formulations. Then, we focus on formulations specifically developed for GBM treatment.", "journal": "Acta biomaterialia", "publication_date": "2020-11-20", "doi": "10.1016/j.actbio.2020.11.030", "authors": [ "Luiza C S Erthal", "Oliviero L Gobbo", "Eduardo Ruiz-Hernandez" ], "keywords": [ "Nanoparticles", "Polymers", "Quality of Life", "Glioblastoma multiforme", "Carmustine", "Glioblastoma", "Injectable hydrogels", "Humans", "Thermo-responsive polymers", "Neoplasm Recurrence, Local", "Chemotherapy", "Brain Neoplasms" ] }, { "pmid": "35569742", "title": "Therapy-induced shaping of the glioblastoma microenvironment: Macrophages at play.", "abstract": "The intricate cross-talks between tumor cells and their microenvironment play a key role in cancer progression and resistance to treatment. In recent years, targeting pro-tumorigenic components of the tumor microenvironment (TME) has emerged as a tantalizing strategy to improve the efficacy of standard-of-care (SOC) treatments, particularly for hard-to-treat cancers such as glioblastoma. In this review, we explore how the distinct microenvironmental niches characteristic of the glioblastoma TME shape response to therapy. In particular, we delve into the interplay between tumor-associated macrophages (TAM) and glioblastoma cells within angiogenic and hypoxic niches, and interrogate their dynamic co-evolution upon SOC therapies that fuels malignancy. Resolving the complexity of therapy-induced alterations in the glioblastoma TME and their impact on disease relapse is a stepping stone to identify targetable pro-tumorigenic pathways and TAM subsets, and may open the way to efficient combination therapies that will improve clinical outcomes.", "journal": "Seminars in cancer biology", "publication_date": "2022-05-13", "doi": "10.1016/j.semcancer.2022.05.003", "authors": [ "Johanna Erbani", "Menno Boon", "Leila Akkari" ], "keywords": [ "Macrophages", "Angiogenesis", "Hypoxia", "Tumor microenvironment", "Carcinogenesis", "Glioblastoma", "Tumor Microenvironment", "Humans" ] }, { "pmid": "37375742", "title": "Current Status and Challenges of Oncolytic Virotherapy for the Treatment of Glioblastoma.", "abstract": "Despite decades of research and numerous clinical trials, the prognosis of patients diagnosed with glioblastoma (GBM) remains dire with median observed survival at 8 months. There is a critical need for novel treatments for GBM, which is the most common malignant primary brain tumor. Major advances in cancer therapeutics such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy have not yet led to improved outcomes for GBM. Conventional therapy of surgery followed by chemoradiation with or without tumor treating fields remains the standard of care. One of the many approaches to GBM therapy currently being explored is viral therapies. These typically work by selectively lysing target neoplastic cells, called oncolysis, or by the targeted delivery of a therapeutic transgene via a viral vector. In this review, we discuss the underlying mechanisms of action and describe both recent and current human clinical trials using these viruses with an emphasis on promising viral therapeutics that may ultimately break the field's current stagnant paradigm.", "journal": "Pharmaceuticals (Basel, Switzerland)", "publication_date": "2023-05-26", "doi": "10.3390/ph16060793", "authors": [ "Mason J Webb", "Ugur Sener", "Richard G Vile" ], "keywords": [ "oncolytic virotherapy", "glioblastoma", "clinical trials" ] }, { "pmid": "34561269", "title": "Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.", "abstract": "Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as \"recruiting\" or \"not yet recruiting\" as of February 2021.", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "publication_date": "2022-02", "doi": "10.1158/1078-0432.CCR-21-2750", "authors": [ "Stephen J Bagley", "Shawn Kothari", "Rifaquat Rahman", "Eudocia Q Lee", "Gavin P Dunn" ], "keywords": [ "Research Design", "Adult", "Glioblastoma", "Humans", "Brain Neoplasms" ] }, { "pmid": "38712663", "title": "Microglia and macrophages in glioblastoma: landscapes and treatment directions.", "abstract": "Glioblastoma is the most common primary malignant tumour of the central nervous system and remains uniformly and rapidly fatal. The tumour-associated macrophage (TAM) compartment comprises brain-resident microglia and bone marrow-derived macrophages (BMDMs) recruited from the periphery. Immune-suppressive and tumour-supportive TAM cell states predominate in glioblastoma, and immunotherapies, which have achieved striking success in other solid tumours have consistently failed to improve survival in this 'immune-cold' niche context. Hypoxic and necrotic regions in the tumour core are found to enrich, especially in anti-inflammatory and immune-suppressive TAM cell states. Microglia predominate at the invasive tumour margin and express pro-inflammatory and interferon TAM cell signatures. Depletion of TAMs, or repolarisation towards a pro-inflammatory state, are appealing therapeutic strategies and will depend on effective understanding and classification of TAM cell ontogeny and state based on new single-cell and spatial multi-omic in situ profiling. Here, we explore the application of these datasets to expand and refine TAM characterisation, to inform improved modelling approaches, and ultimately underpin the effective manipulation of function.", "journal": "Molecular oncology", "publication_date": "2024-05-07", "doi": "10.1002/1878-0261.13657", "authors": [ "Georgios Solomou", "Adam M H Young", "Harry J C J Bulstrode" ], "keywords": [ "glioma", "Animals", "Immunotherapy", "Macrophages", "Tumor-Associated Macrophages", "immune", "glioblastoma", "microglia", "Microglia", "Glioblastoma", "Tumor Microenvironment", "Humans", "macrophages", "Brain Neoplasms", "microenvironment" ] }, { "pmid": "36831702", "title": "Clinical Effects of Immuno-Oncology Therapy on Glioblastoma Patients: A Systematic Review.", "abstract": "The most prevalent and deadly primary malignant glioma in adults is glioblastoma (GBM), which has a median survival time of about 15 months. Despite the standard of care for glioblastoma, which includes gross total resection, high-dose radiation, and temozolomide chemotherapy, this tumor is still one of the most aggressive and difficult to treat. So, it is critical to find more potent therapies that can help glioblastoma patients have better clinical outcomes. Additionally, the prognosis for recurring malignant gliomas is poor, necessitating the need for innovative therapeutics. Immunotherapy is a rather new treatment for glioblastoma and its effects are not well studied when it is combined with standard chemoradiation therapy. We conducted this study to evaluate different glioblastoma immunotherapy approaches in terms of feasibility, efficacy, and safety. We conducted a computer-assisted literature search of electronic databases for essays that are unique, involve either prospective or retrospective research, and are entirely written and published in English. We examined both observational data and randomized clinical trials. Eighteen studies met the criteria for inclusion. In conclusion, combining immunotherapy with radiochemotherapy and tumor removal is generally possible and safe, and rather effective in the prolongation of survival measures.", "journal": "Brain sciences", "publication_date": "2023-01-17", "doi": "10.3390/brainsci13020159", "authors": [ "Masoumeh Najafi", "Amin Jahanbakhshi", "Sebastiano Finocchi Ghersi", "Lucia Giaccherini", "Andrea Botti" ], "keywords": [ "chemotherapy", "radiotherapy", "vaccine", "cell therapy", "immuno-oncologic therapy", "GBM", "glioblastoma", "oncolytic viral therapy", "temozolomide", "immunotherapy", "cell-based therapy", "vaccination", "check-point inhibitor" ] }, { "pmid": "37046777", "title": "Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM).", "abstract": "Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of conventional treatments through mechanisms such as increased resistance to cell death and rapid regeneration of cancerous cells. Additionally, the blood-brain barrier makes it difficult for chemotherapy drugs to reach GBM cells, leading to reduced effectiveness. Despite these challenges, there are several treatment options available for GBM. The standard of care for newly diagnosed GBM patients involves surgical resection followed by concurrent chemoradiotherapy and adjuvant chemotherapy. Emerging treatments include immunotherapy, such as checkpoint inhibitors, and targeted therapies, such as bevacizumab, that attempt to attack specific vulnerabilities in GBM cells. Another promising approach is the use of tumor-treating fields, a type of electric field therapy that has been shown to slow the growth of GBM cells. Clinical trials are ongoing to evaluate the safety and efficacy of these and other innovative treatments for GBM, intending to improve with outcomes for patients.", "journal": "Cancers", "publication_date": "2023-04-01", "doi": "10.3390/cancers15072116", "authors": [ "Satya Siva Kishan Yalamarty", "Nina Filipczak", "Xiang Li", "Md Abdus Subhan", "Farzana Parveen" ], "keywords": [ "glioblastoma multiforme", "drug delivery systems", "immunotherapy", "nanomedicine", "resistance" ] }, { "pmid": "35096619", "title": "Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma.", "abstract": "Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.", "journal": "Frontiers in oncology", "publication_date": "2022-01-12", "doi": "10.3389/fonc.2021.812916", "authors": [ "Saket Jain", "Eric J Chalif", "Manish K Aghi" ], "keywords": [ "glioma", "glioblastoma", "anti-angiogenic therapy", "bevacizumab", "immunotherapy", "combinatorial therapy", "checkpoint inhibitors" ] }, { "pmid": "36291865", "title": "Radiomic and Volumetric Measurements as Clinical Trial Endpoints-A Comprehensive Review.", "abstract": "Clinical trials for oncology drug development have long relied on surrogate outcome biomarkers that assess changes in tumor burden to accelerate drug registration (i.e., Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria). Drug-induced reduction in tumor size represents an imperfect surrogate marker for drug activity and yet a radiologically determined objective response rate is a widely used endpoint for Phase 2 trials. With the addition of therapies targeting complex biological systems such as immune system and DNA damage repair pathways, incorporation of integrative response and outcome biomarkers may add more predictive value. We performed a review of the relevant literature in four representative tumor types (breast cancer, rectal cancer, lung cancer and glioblastoma) to assess the preparedness of volumetric and radiomics metrics as clinical trial endpoints. We identified three key areas-segmentation, validation and data sharing strategies-where concerted efforts are required to enable progress of volumetric- and radiomics-based clinical trial endpoints for wider clinical implementation.", "journal": "Cancers", "publication_date": "2022-10-17", "doi": "10.3390/cancers14205076", "authors": [ "Ionut-Gabriel Funingana", "Pubudu Piyatissa", "Marika Reinius", "Cathal McCague", "Bristi Basu" ], "keywords": [ "imaging biomarkers", "volumetric", "radiomics", "clinical trials", "surrogate endpoints", "data integration" ] }, { "pmid": "34274381", "title": "Antioxidant responses related to temozolomide resistance in glioblastoma.", "abstract": "Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.", "journal": "Neurochemistry international", "publication_date": "2021-07-16", "doi": "10.1016/j.neuint.2021.105136", "authors": [ "José A Campos-Sandoval", "María C Gómez-García", "Juan de Los Santos-Jiménez", "José M Matés", "Francisco J Alonso" ], "keywords": [ "Animals", "Antineoplastic Agents, Alkylating", "Antioxidants", "Neoplastic Stem Cells", "Antioxidant", "Reactive Oxygen Species", "ROS", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "39534539", "title": "The landscape of immune checkpoint inhibitor clinical trials in glioblastoma: A systematic review.", "abstract": "BACKGROUND: Glioblastoma is characterized by rapid tumor growth and high invasiveness. The tumor microenvironment of glioblastoma is highly immunosuppressive with both intrinsic and adaptive resistance mechanisms that result in disease recurrence despite current immunotherapeutic strategies. METHODS: In this systematic review of clinical trials involving immunotherapy for glioblastoma using ClinicalTrials.gov and PubMed databases from 2016 and onward, we explore immunotherapeutic modalities involving immune checkpoint blockade (ICB). RESULTS: A total of 106 clinical trials were identified, 18 with clinical outcomes. ICB in glioblastoma has failed to improve overall survival compared to the current standard of care, including those therapies inhibiting multiple checkpoints. Among all immune checkpoint trials, targets included programmed cell death protein-1 (PD-1) (35/48), PD-L1 (12/48), cytotoxic T-lymphocyte-associated protein-4 (6/48), TIGIT (2/48), B7-H3 (2/48), and TIM-3 (1/48). Preliminary results from combination immunotherapies (32.1% of all trials) demonstrated improved treatment efficacy compared to monotherapy, specifically those combining checkpoint therapy with another immunotherapy modality. CONCLUSIONS: Clinical trials involving ICB strategies for glioblastoma have not demonstrated improved survival. Comparison of therapeutic efficacy across trials was limited due to heterogeneity in the study population and outcome operationalization. Standardization of future trials could facilitate comparison across immunotherapy modalities for robust meta-analysis. Current immunotherapy trials have shifted focus toward combination strategies; preliminary results suggest that they are more encouraging than mono-modality immunotherapies. Given the intrinsic heterogeneity of glioblastoma, the utilization of immune markers will be key for the development of future immunotherapy approaches.", "journal": "Neuro-oncology advances", "publication_date": "2024-11-12", "doi": "10.1093/noajnl/vdae174", "authors": [ "Ethan Schonfeld", "John Choi", "Andrew Tran", "Lily H Kim", "Michael Lim" ], "keywords": [ "clinical trial", "glioblastoma", "combination therapy", "immunotherapy", "immune marker" ] }, { "pmid": "34335972", "title": "A perspective on the radiopharmaceutical requirements for imaging and therapy of glioblastoma.", "abstract": "Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular.", "journal": "Theranostics", "publication_date": "2021-07-06", "doi": "10.7150/thno.56639", "authors": [ "Julie Bolcaen", "Janke Kleynhans", "Shankari Nair", "Jeroen Verhoeven", "Ingeborg Goethals" ], "keywords": [ "Radioisotopes", "Precision Medicine", "radiochemistry", "glioblastoma", "theranostics", "Radiopharmaceuticals", "Glioblastoma", "targeted radionuclide therapy", "Humans", "PET SPECT imaging" ] }, { "pmid": "34214730", "title": "Progress and prospect in tumor treating fields treatment of glioblastoma.", "abstract": "Glioblastoma (GBM) is a challenging cancer with poor prognosis. The classical standard for treatment is safe resection, followed by concurrent chemoradiotherapy with subsequent adjuvant temozolomide (TMZ). Despite several attempts at different treatments, the 5-year survival rate remains poor. In recent years, with the continuous progress of treatment technology, tumor treating fields (TTFields) were preferable. The device could generate an intermediate frequency alternating electric field and induce apoptosis of some specific types of cancer cells with few toxic and side effects. TTFields induced apoptosis through multiple activations of the pathway. TTFields have been Food and Drug Administration (FDA)-approved for diagnosis and recurrent GBM as additional clinical trial results are revealed. This study reviewed the current status, mechanisms, correlations with immune pathways, the prospects of applying TTFields for GBM, and the adverse events.", "journal": "Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie", "publication_date": "2021-06-30", "doi": "10.1016/j.biopha.2021.111810", "authors": [ "Shiyu Liu", "Weiyan Shi", "Qin Zhao", "Zhuangzhuang Zheng", "Zijing Liu" ], "keywords": [ "Tumor treating fields", "Animals", "Antineoplastic Agents, Alkylating", "Temozolomide", "Combined Modality Therapy", "Adverse events", "Chemoradiotherapy", "Glioblastoma", "Humans", "Neoplasm Recurrence, Local", "Radiotherapy", "Brain Neoplasms", "Neurosurgical Procedures" ] }, { "pmid": "38180686", "title": "Understanding current experimental models of glioblastoma-brain microenvironment interactions.", "abstract": "Glioblastoma (GBM) is a common and devastating primary brain tumor, with median survival of 16-18 months after diagnosis in the setting of substantial resistance to standard-of-care and inevitable tumor recurrence. Recent work has implicated the brain microenvironment as being critical for GBM proliferation, invasion, and resistance to treatment. GBM does not operate in isolation, with neurons, astrocytes, and multiple immune populations being implicated in GBM tumor progression and invasiveness. The goal of this review article is to provide an overview of the available in vitro, ex vivo, and in vivo experimental models for assessing GBM-brain interactions, as well as discuss each model's relative strengths and limitations. Current in vitro models discussed will include 2D and 3D co-culture platforms with various cells of the brain microenvironment, as well as spheroids, whole organoids, and models of fluid dynamics, such as interstitial flow. An overview of in vitro and ex vivo organotypic GBM brain slices is also provided. Finally, we conclude with a discussion of the various in vivo rodent models of GBM, including xenografts, syngeneic grafts, and genetically-engineered models of GBM.", "journal": "Journal of neuro-oncology", "publication_date": "2024-01-05", "doi": "10.1007/s11060-023-04536-8", "authors": [ "Niket Yadav", "Benjamin W Purow" ], "keywords": [ "GBM models", "Brain", "Tumor microenvironment", "Models, Theoretical", "Glioblastoma", "Tumor Microenvironment", "Humans", "Cell Line, Tumor", "Neoplasm Recurrence, Local", "Brain Neoplasms" ] }, { "pmid": "36096529", "title": "LRIG2 promotes glioblastoma progression by modulating innate antitumor immunity through macrophage infiltration and polarization.", "abstract": "BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical outcomes. Immunotherapy has recently been an attractive and promising treatment of extracranial malignancies, however, most of clinical trials for GBM immunotherapy failed due to predominant accumulation of tumor-associated microglia/macrophages (TAMs). RESULTS: High level of LRIG2/soluble LRIG2 (sLRIG2) expression activates immune-related signaling pathways, which are associated with poor prognosis in GBM patients. LRIG2/sLRIGs promotes CD47 expression and facilitates TAM recruitment. Blockade of CD47-SIRPα interactions and inhibition of sLRIG2 secretion synergistically suppress GBM progression in an orthotropic murine GBM model. CONCLUSIONS: GBM cells with high level LRIG2 escape the phagocytosis by TAM via the CD47-SIRPα axis, highlighting a necessity for an early stage of clinical trial targeting LRIG2 and CD47-SIRPα as a novel treatment for patients with GBM.", "journal": "Journal for immunotherapy of cancer", "publication_date": "2022-09", "doi": "10.1136/jitc-2021-004452", "authors": [ "Jinyang Hu", "Feng Dong", "You He", "Xianyou Xia", "Fangling Cheng" ], "keywords": [ "CD47 Antigen", "Animals", "Immunity, Innate", "Macrophages", "Mice", "Membrane Glycoproteins", "Phagocytosis", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "38927583", "title": "Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies.", "abstract": "Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12-16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor treatment, largely due to the formidable barrier posed by the blood-brain barrier. The current standard of care involves a multifaceted approach combining surgery, irradiation, and chemotherapy. However, recurrence often occurs within months despite these interventions. The formidable challenges of drug delivery to the brain and overcoming therapeutic resistance have become focal points in the treatment of brain tumors and are deemed essential to overcoming tumor recurrence. In recent years, a promising wave of advanced treatments has emerged, offering a glimpse of hope to overcome the limitations of existing therapies. This review aims to highlight cutting-edge technologies in the current and ongoing stages of development, providing patients with valuable insights to guide their choices in brain tumor treatment.", "journal": "Biomedicines", "publication_date": "2024-06-20", "doi": "10.3390/biomedicines12061376", "authors": [ "Trang T T Nguyen", "Lloyd A Greene", "Hayk Mnatsakanyan", "Christian E Badr" ], "keywords": [ "targeted therapy", "glioblastoma multiforme", "fMRI", "gene and cell therapy", "temozolomide", "TTFields", "immunotherapy", "external beam radiation therapy", "artificial intelligence (AI)" ] }, { "pmid": "40784815", "title": "Therapeutic potential of targeting macrophages and microglia in glioblastoma.", "abstract": "Glioblastoma (GBM) is a highly aggressive and lethal form of brain tumor in human adults that resists standard of care (SOC) and immunotherapy. Tumor-associated macrophages and microglia (TAMs) represent the most abundant cell population within the GBM tumor microenvironment (TME), comprising up to 50% of the whole tumor mass. TAMs play a pivotal role in promoting tumor progression, driving immunosuppression and inducing therapy resistance. Recent advances have revealed TAM heterogeneity - including their cellular identity (e.g., bone marrow-derived macrophages versus microglia) and the presence of distinct activation/function states and subpopulations within each subtype - in GBM tumors. Targeting the context-dependent TAM infiltration, reprogramming, new subpopulations, survival, phagocytosis, and their interactions with GBM cells in the TME has emerged as a promising therapeutic strategy. Herein we review recent advances in pharmacological targeting of the TAM biology and highlight how these strategies may enhance the effectiveness of SOC and immunotherapies in GBM.", "journal": "Trends in pharmacological sciences", "publication_date": "2025-08-09", "doi": "10.1016/j.tips.2025.07.006", "authors": [ "Fei Zhou", "Pritha Mukherjee", "Jinming Mu", "Peiwen Chen" ], "keywords": [ "Animals", "Immunotherapy", "Macrophages", "Tumor-Associated Macrophages", "glioblastoma", "tumor microenvironment (TME)", "immunotherapy", "Microglia", "Glioblastoma", "Tumor Microenvironment", "Humans", "tumor-associated macrophages and microglia (TAMs)", "Brain Neoplasms" ] }, { "pmid": "36805210", "title": "Modeling glioblastoma complexity with organoids for personalized treatments.", "abstract": "Glioblastoma (GBM) remains a fatal diagnosis despite the current standard of care of maximal surgical resection, radiation, and temozolomide (TMZ) therapy. One aspect that impedes drug development is the lack of an appropriate model representative of the complexity of patient tumors. Brain organoids derived from cell culture techniques provide a robust, easily manipulatable, and high-throughput model for GBM. In this review, we highlight recent progress in developing GBM organoids (GBOs) with a focus on generating the GBM microenvironment (i.e., stem cells, vasculature, and immune cells) recapitulating human disease. Finally, we also discuss the use of organoids as a screening tool in drug development for GBM.", "journal": "Trends in molecular medicine", "publication_date": "2023-02-15", "doi": "10.1016/j.molmed.2023.01.002", "authors": [ "Kristen D Pawlowski", "Joseph T Duffy", "Maria V Babak", "Irina V Balyasnikova" ], "keywords": [ "tumor microenvironment", "Cell Culture Techniques", "Organoids", "brain organoids", "glioblastoma", "drug screening", "Tumor Microenvironment", "Glioblastoma", "Drug Resistance, Neoplasm", "Humans", "Cell Line, Tumor", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "34623599", "title": "Leptomeningeal disease in glioblastoma: endgame or opportunity?", "abstract": "INTRODUCTION: Glioblastoma is an aggressive cancer with a notoriously poor prognosis. Recent advances in treatment have increased overall survival, though this may be accompanied by an increased incidence of leptomeningeal disease (LMD). LMD carries a particularly severe prognosis and remains a late stage manifestation of glioblastoma without satisfactory treatment. The objective of this review is to survey the literature on treatment of LMD in glioblastoma and to more fully characterize the current therapeutic strategies. METHODS: The authors performed a systematic review following PRISMA criteria on PubMed and OVID databases. Articles that included adult patients with LMD from glioblastoma were retrieved and reviewed. RESULTS: LMD in glioblastoma patients is increasing in incidence, with reports of up to 21%. The overall survival without treatment is alarmingly brief, with patients surviving between 1.6-3.8 months. All studies showed that treatment does improve overall survival significantly, increasing to 11.7 months in one study. However, no one adjuvant or surgical therapy has been shown to improve survival in LMD significantly over another. Direct treatment methods include chemotherapy (standard, anti-angiogenic, intrathecal, immunotherapy), and radiation. Hydrocephalus is a complication in LMD that can be treated with ventriculoperitoneal shunt placement, however treating hydrocephalus and delivering intrathecal chemotherapy is a challenge. CONCLUSION: Though evidence remains lacking and there is no consensus, treatments show a trend towards improving survival and should be considered on a case-by-case basis. Further studies are necessary in the pursuit of a standard of care.", "journal": "Journal of neuro-oncology", "publication_date": "2021-10-08", "doi": "10.1007/s11060-021-03864-x", "authors": [ "Sarfraz Akmal", "Elizabeth E Ginalis", "Nitesh V Patel", "Robert Aiken", "Alis J Dicpinigaitis" ], "keywords": [ "Leptomeningeal disease", "Neuro-oncology", "Meningeal Neoplasms", "Prognosis", "Glioblastoma", "Humans", "Leptomeningeal metastasis" ] }, { "pmid": "36230883", "title": "Advances in Preclinical/Clinical Glioblastoma Treatment: Can Nanoparticles Be of Help?", "abstract": "Glioblastoma multiforme (GB) is the most aggressive and frequent primary malignant tumor in the central nervous system (CNS), with unsatisfactory and challenging treatment nowadays. Current standard of care includes surgical resection followed by chemotherapy and radiotherapy. However, these treatments do not much improve the overall survival of GB patients, which is still below two years (the 5-year survival rate is below 7%). Despite various approaches having been followed to increase the release of anticancer drugs into the brain, few of them demonstrated a significant success, as the blood brain barrier (BBB) still restricts its uptake, thus limiting the therapeutic options. Therefore, enormous efforts are being devoted to the development of novel nanomedicines with the ability to cross the BBB and specifically target the cancer cells. In this context, the use of nanoparticles represents a promising non-invasive route, allowing to evade BBB and reducing systemic concentration of drugs and, hence, side effects. In this review, we revise with a critical view the different families of nanoparticles and approaches followed so far with this aim.", "journal": "Cancers", "publication_date": "2022-10-10", "doi": "10.3390/cancers14194960", "authors": [ "Daniel Ruiz-Molina", "Xiaoman Mao", "Paula Alfonso-Triguero", "Julia Lorenzo", "Jordi Bruna" ], "keywords": [ "drug delivery", "BBB", "preclinical model", "glioblastoma", "brain cancer", "nanoparticles" ] }, { "pmid": "39609830", "title": "The neglected burden of chronic hypoxia on the resistance of glioblastoma multiforme to first-line therapies.", "abstract": "Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1-2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.", "journal": "BMC biology", "publication_date": "2024-11-28", "doi": "10.1186/s12915-024-02075-w", "authors": [ "Jolie Bou-Gharios", "Georges Noël", "Hélène Burckel" ], "keywords": [ "HIF-1α", "Tumor Hypoxia", "Glioblastoma multiforme", "HIF-2α", "Hypoxia", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "Proteomics", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "35677164", "title": "Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment.", "abstract": "Glioblastoma is one of the central nervous system most aggressive and lethal cancers with poor overall survival rate. Systemic treatment of glioblastoma remains the most challenging aspect due to the low permeability of the blood-brain barrier (BBB) and blood-tumor barrier (BTB), limiting therapeutics extravasation mainly in the core tumor as well as in its surrounding invading areas. It is now possible to overcome these barriers by using low-intensity focused ultrasound (LIFU) together with intravenously administered oscillating microbubbles (MBs). LIFU is a non-invasive technique using converging ultrasound waves which can alter the permeability of BBB/BTB to drug delivery in a specific brain/tumor region. This emerging technique has proven to be both safe and repeatable without causing injury to the brain parenchyma including neurons and other structures. Furthermore, LIFU is also approved by the FDA to treat essential tremors and Parkinson's disease. It is currently under clinical trial in patients suffering from glioblastoma as a drug delivery strategy and liquid biopsy for glioblastoma biomarkers. The use of LIFU+MBs is a step-up in the world of drug delivery, where onco-therapeutics of different molecular sizes and weights can be delivered directly into the brain/tumor parenchyma. Initially, several potent drugs targeting glioblastoma were limited to cross the BBB/BTB; however, using LIFU+MBs, diverse therapeutics showed significantly higher uptake, improved tumor control, and overall survival among different species. Here, we highlight the therapeutic approach of LIFU+MBs mediated drug-delivery in the treatment of glioblastoma.", "journal": "Frontiers in oncology", "publication_date": "2022-05-19", "doi": "10.3389/fonc.2022.903059", "authors": [ "Rajneesh Mungur", "Jiesheng Zheng", "Ben Wang", "Xinhua Chen", "Renya Zhan" ], "keywords": [ "drug-delivery", "glioblastoma", "blood-tumor barrier (BTB)", "low-intensity focused ultrasound", "blood-brain barrier" ] }, { "pmid": "33810154", "title": "Current FDA-Approved Therapies for High-Grade Malignant Gliomas.", "abstract": "The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.", "journal": "Biomedicines", "publication_date": "2021-03-22", "doi": "10.3390/biomedicines9030324", "authors": [ "Jacob P Fisher", "David C Adamson" ], "keywords": [ "high-grade glioma", "tumor treatment fields", "malignant glioma", "glioblastoma", "bevacizumab", "FDA-approved", "temozolomide", "standard of care", "carmustine", "lomustine" ] }, { "pmid": "33435537", "title": "Updated Insights on EGFR Signaling Pathways in Glioma.", "abstract": "Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.", "journal": "International journal of molecular sciences", "publication_date": "2021-01-08", "doi": "10.3390/ijms22020587", "authors": [ "Alexandru Oprita", "Stefania-Carina Baloi", "Georgiana-Adeline Staicu", "Oana Alexandru", "Daniela Elise Tache" ], "keywords": [ "glioma", "pathways", "Antineoplastic Agents, Alkylating", "Temozolomide", "Combined Modality Therapy", "EGFR", "Gene Expression Regulation, Neoplastic", "clinical trials", "ErbB Receptors", "Glioblastoma", "Humans", "Glioma", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "38067356", "title": "Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma.", "abstract": "Glioblastoma (GBM), the most common primary brain tumor in adults, is characterized by low survival rates and a grim prognosis. Current treatment modalities, including extensive surgical resection, chemotherapy, and radiation therapy, often yield limited success due to the brain's sensitivity, leading to significant side effects. Exciting advancements in immunotherapy have recently shown promise in treating various types of tumors, raising hopes for improved outcomes in brain tumor patients. One promising immunotherapy approach is chimeric antigen receptor (CAR) T-cell therapy, which recognizes surface proteins on targeted tumor cells and redirects cytotoxicity towards specific targets. This review aims to discuss the existing research and future prospects for CAR T-cell immunotherapy in treating glioblastoma.", "journal": "Cancers", "publication_date": "2023-11-30", "doi": "10.3390/cancers15235652", "authors": [ "Kun Ma", "Ping Hu" ], "keywords": [ "tumor microenvironment", "clinical trial", "tumor heterogeneity", "glioblastoma", "CAR T-cell therapy", "oncolytic virus" ] }, { "pmid": "38090060", "title": "Progress in phase III clinical trials of molecular targeted therapy and immunotherapy for glioblastoma.", "abstract": "Glioblastoma (GBM) is the most common primary central nervous system tumor, whose prognosis remains poor under the sequential standard of care, such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields. Accordingly, the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management. A diverse range of targeted drugs have been tested in patients with GBM in phase III clinical trials. However, these drugs are ineffective for all patients, as evidenced by the fact that only a minority of patients in these trials showed prolonged survival. Furthermore, there are several published phase III clinical trials that involve immune checkpoint inhibitors, peptide vaccines, dendritic cell vaccines, and virotherapy. Accordingly, this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.", "journal": "Cancer innovation", "publication_date": "2023-03-05", "doi": "10.1002/cai2.59", "authors": [ "Yuekun Wang", "Shenglan Li", "Yichen Peng", "Wenbin Ma", "Yu Wang" ], "keywords": [ "immunotherapy", "target therapy", "glioblastoma", "phase III clinical trial" ] }, { "pmid": "37182666", "title": "Multiple therapeutic approaches of glioblastoma multiforme: From terminal to therapy.", "abstract": "Glioblastoma multiforme (GBM) is an aggressive brain cancer showing poor prognosis. Currently, treatment methods of GBM are limited with adverse outcomes and low survival rate. Thus, advancements in the treatment of GBM are of utmost importance, which can be achieved in recent decades. However, despite aggressive initial treatment, most patients develop recurrent diseases, and the overall survival rate of patients is impossible to achieve. Currently, researchers across the globe target signaling events along with tumor microenvironment (TME) through different drug molecules to inhibit the progression of GBM, but clinically they failed to demonstrate much success. Herein, we discuss the therapeutic targets and signaling cascades along with the role of the organoids model in GBM research. Moreover, we systematically review the traditional and emerging therapeutic strategies in GBM. In addition, we discuss the implications of nanotechnologies, AI, and combinatorial approach to enhance GBM therapeutics.", "journal": "Biochimica et biophysica acta. Reviews on cancer", "publication_date": "2023-05-12", "doi": "10.1016/j.bbcan.2023.188913", "authors": [ "Smita Kumari", "Rohan Gupta", "Rashmi K Ambasta", "Pravir Kumar" ], "keywords": [ "Organoid models", "Artificial intelligence", "Combinatorial therapy", "Glioblastoma multiforme", "Personalized medicine", "Glioblastoma", "Tumor Microenvironment", "Humans", "Nanotheranostic", "Therapeutic strategies", "Signal Transduction" ] }, { "pmid": "34053034", "title": "Overcoming delivery barriers in immunotherapy for glioblastoma.", "abstract": "Glioblastoma is one of the deadliest forms of primary adult tumors, with median survival of 14.6 months post-diagnosis despite aggressive standard of care treatment. This grim prognosis for glioblastoma patients has changed little in the past two decades, necessitating novel treatment modalities. One potential treatment modality is cancer immunotherapy, which has shown remarkable progress in slowing disease progression or even potentially curing certain solid tumors. However, the transport barriers posed by the blood-brain barrier and the immune privileged status of the central nervous system pose drug delivery obstacles that are unique to brain tumors. In this review, we provide an overview of the various physiological, immunological, and drug delivery barriers that must be overcome for effective glioblastoma treatment. We discuss chemical modification strategies to enable nanomedicines to bypass the blood-brain barrier and reach intracranial tumors. Finally, we highlight recent advances in biomaterial-based strategies for cancer immunotherapy that can be adapted to glioblastoma treatment.", "journal": "Drug delivery and translational research", "publication_date": "2021-05-30", "doi": "10.1007/s13346-021-01008-2", "authors": [ "Yuan Rui", "Jordan J Green" ], "keywords": [ "Blood-Brain Barrier", "Immunotherapy", "Adult", "Blood–brain barrier", "Drug delivery", "Glioblastoma", "Humans", "Drug Delivery Systems", "Nanomedicine", "Brain Neoplasms" ] }, { "pmid": "34036721", "title": "DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies.", "abstract": "Glioblastoma is the most frequently diagnosed type of primary brain tumour in adults. These aggressive tumours are characterised by inherent treatment resistance and disease progression, contributing to ~ 190 000 brain tumour-related deaths globally each year. Current therapeutic interventions consist of surgical resection followed by radiotherapy and temozolomide chemotherapy, but average survival is typically around 1 year, with < 10% of patients surviving more than 5 years. Recently, a fourth treatment modality of intermediate-frequency low-intensity electric fields [called tumour-treating fields (TTFields)] was clinically approved for glioblastoma in some countries after it was found to increase median overall survival rates by ~ 5 months in a phase III randomised clinical trial. However, beyond these treatments, attempts to establish more effective therapies have yielded little improvement in survival for patients over the last 50 years. This is in contrast to many other types of cancer and highlights glioblastoma as a recognised tumour of unmet clinical need. Previous work has revealed that glioblastomas contain stem cell-like subpopulations that exhibit heightened expression of DNA damage response (DDR) factors, contributing to therapy resistance and disease relapse. Given that radiotherapy, chemotherapy and TTFields-based therapies all impact DDR mechanisms, this Review will focus on our current knowledge of the role of the DDR in glioblastoma biology and treatment. We also discuss the potential of effective multimodal targeting of the DDR combined with standard-of-care therapies, as well as emerging therapeutic targets, in providing much-needed improvements in survival rates for patients.", "journal": "Molecular oncology", "publication_date": "2021-06-11", "doi": "10.1002/1878-0261.13020", "authors": [ "Ola Rominiyi", "Spencer J Collis" ], "keywords": [ "Clinical Trials, Phase III as Topic", "DNA damage response", "chemotherapy", "radiotherapy", "synthetic lethality", "Adult", "DNA Damage", "Combined Modality Therapy", "Randomized Controlled Trials as Topic", "glioblastoma", "tumour-treating fields", "Glioblastoma", "Humans", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "39346903", "title": "Radiation immunodynamics in patients with glioblastoma receiving chemoradiation.", "abstract": "INTRODUCTION: This is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease. METHODS: 16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics. RESULTS: We identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8+ T lymphocytes that produced IFNγ, the potent anti-tumor cytokine. DISCUSSION: These data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.", "journal": "Frontiers in immunology", "publication_date": "2024-09-13", "doi": "10.3389/fimmu.2024.1438044", "authors": [ "Lindsey Sloan", "Rupashree Sen", "Chunnan Liu", "Michele Doucet", "Lee Blosser" ], "keywords": [ "glioblastoma", "Glioblastoma", "Humans", "Male", "immune system", "Myeloid-Derived Suppressor Cells", "Middle Aged", "chemoradiotherapy", "Female", "Temozolomide", "radiotherapy", "Adult", "Prospective Studies", "Aged", "CD8-Positive T-Lymphocytes", "Chemoradiotherapy", "brain tumor", "Tumor Microenvironment", "Brain Neoplasms" ] }, { "pmid": "40120123", "title": "A multi-institutional phase 1 clinical trial exploring upfront multimodal standard of care and combined immunotherapies for newly diagnosed glioblastoma.", "abstract": "BACKGROUND: For newly diagnosed glioblastoma (GBM), combination of surgical upfront immunotherapy with aglatimagene besadenovec (CAN-2409), followed by chemoradiation and then adjuvant nivolumab has not been tested. The aim of this study was to test the safety of this regimen and determine metrics of immune activation that may correlate with clinical outcomes. METHODS: 41 patients with suspected newly diagnosed GBM by imaging were enrolled in this multi-institutional, open label, phase 1b clinical trial before surgical resection. Frozen section confirmation of high-grade glioma was required for administration of aglatimagene besadenovec. This was then followed with chemoradiation and adjuvant nivolumab. Tumor and blood were assayed for genetic and immune markers before and during treatment. RESULTS: The regimen was well tolerated and generated measurable immune activation. Factors linked to survival were identified, such as baseline mutated gene pairs (e.g. MED15/ HRC), tumor immune cell composition, and changes in systemic cytokine, immune cells, and T cell diversity. The most significant serial systemic immune changes were observed in a long-term survivor subset of patients with gross total resection (GTR)/ methylated methylguanine methyltransferase (MGMT) promoter tumors. Median overall survival (mOS) in these patients was 30.6 months, while it was less for patients with unmethylated or subtotal resections. CONCLUSIONS: These findings suggest the opportunity for patient stratification and the potential for more durable antitumor immune responses in future clinical trials of this multimodal standard of care and combined immunotherapy regimen. ClinicalTrials.gov identifier: NCT03576612.", "journal": "Neuro-oncology", "publication_date": "2025-03-22", "doi": "10.1093/neuonc/noaf079", "authors": [ "Patrick Y Wen", "Andrea Manzanera", "Caroline Duault", "Edgar Gonzalez-Kozlova", "Lenika Lopez" ], "keywords": [ "glioma", "Clinical trial", "gene therapy", "brain tumor", "immunotherapy" ] }, { "pmid": "37399061", "title": "Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.", "abstract": "BACKGROUND: Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. METHODS: The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. RESULTS: We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. CONCLUSION: Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.", "journal": "Neuro-oncology", "publication_date": "2023-12", "doi": "10.1093/neuonc/noad117", "authors": [ "Evan K Noch", "Laura N Palma", "Isaiah Yim", "Nayah Bullen", "Yuqing Qiu" ], "keywords": [ "Animals", "Metformin", "glioblastoma", "Glioblastoma", "hyperglycemia", "Humans", "Feedback", "Hypoglycemic Agents", "Hyperglycemia", "Phosphatidylinositol 3-Kinases", "Retrospective Studies", "Phosphatidylinositol 3-Kinase", "phosphatidylinositol 3-kinase", "insulin", "Cell Line, Tumor", "Insulin", "Mice", "metformin", "Cell Proliferation", "Tumor Microenvironment" ] }, { "pmid": "38067354", "title": "Hypofractionation in Glioblastoma: An Overview of Palliative, Definitive, and Exploratory Uses.", "abstract": "Glioblastoma (GBM) is the most common primary brain malignancy in adults, and its incidence is increasing worldwide. Its prognosis remains limited despite recent imaging and therapeutic advances. The current standard of care is maximal safe resection followed by conventionally fractionated radiotherapy with concurrent and adjuvant temozolomide (TMZ), with or without tumor-treating fields (TTF). However, hypofractionated radiotherapy (HFRT) has also been utilized for a variety of reasons. It is an established treatment option in the palliative setting, where shortened treatment duration can positively impact the overall quality of life for older patients or those with additional health or socioeconomic considerations. HFRT, and in particular stereotactic radiosurgery (SRS), has also been explored in both the pre- and post-operative setting for newly diagnosed and recurrent diseases. In this review, we summarize the ways in which HFRT has been utilized in the GBM patient population and its evolving role in the experimental space. We also provide commentary on scenarios in which HFRT may be indicated, as well as guidance on dose and fractionation regimens informed by our institutional experience.", "journal": "Cancers", "publication_date": "2023-11-29", "doi": "10.3390/cancers15235650", "authors": [ "Cecilia Jiang", "Casey Mogilevsky", "Zayne Belal", "Goldie Kurtz", "Michelle Alonso-Basanta" ], "keywords": [ "radiotherapy", "glioblastoma", "recurrence", "radiomics", "stereotactic", "hypofractionation", "elderly", "palliation", "FLASH" ] }, { "pmid": "39409905", "title": "Unveiling the Inflammatory Landscape of Recurrent Glioblastoma through Histological-Based Assessments.", "abstract": "The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia (GAMMs) overwhelmingly constitute the bulk of the recurrent glioblastoma (rGBM) microenvironment, in comparison to the highly cellular and proliferative tumor microenvironment characteristic of primary GBM. These immune cells dynamically interact within the tumor microenvironment and can contribute to disease progression and therapy resistance while also providing novel targets for emerging immunotherapies. Within these varying contexts, histological-based assessments of immune cells in rGBM, including immunohistochemistry (IHC) and immunofluorescence (IF), offer a critical way to visualize and examine the inflammatory landscape. Here, we exhaustively review the available body of literature on the inflammatory landscape in rGBM as identified through histological-based assessments. We highlight the heterogeneity of immune cells throughout the glioma-infiltrated cortex with a focus on microglia and macrophages, drawing insights from canonical and novel immune-cell histological markers to estimate cell phenotypes and function. Lastly, we discuss opportunities for immunomodulatory treatments aiming to harness the inflammatory landscape in rGBM.", "journal": "Cancers", "publication_date": "2024-09-26", "doi": "10.3390/cancers16193283", "authors": [ "Nicholas B Dadario", "Deborah M Boyett", "Damian E Teasley", "Peter J Chabot", "Nathan J Winans" ], "keywords": [ "tumor microenvironment", "recurrent glioblastoma", "histology", "immune cells", "microglia", "macrophages" ] }, { "pmid": "37215952", "title": "Current approaches in enhancing TRAIL therapies in glioblastoma.", "abstract": "Glioblastoma (GBM) is the most prevalent, aggressive, primary brain cancer in adults and continues to pose major medical challenges due in part to its high rate of recurrence. Extensive research is underway to discover new therapies that target GBM cells and prevent the inevitable recurrence in patients. The pro-apoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted attention as an ideal anticancer agent due to its ability to selectively kill cancer cells with minimal toxicity in normal cells. Although initial clinical evaluations of TRAIL therapies in several cancers were promising, later stages of clinical trial results indicated that TRAIL and TRAIL-based therapies failed to demonstrate robust efficacies due to poor pharmacokinetics, resulting in insufficient concentrations of TRAIL at the therapeutic site. However, recent studies have developed novel ways to prolong TRAIL bioavailability at the tumor site and efficiently deliver TRAIL and TRAIL-based therapies using cellular and nanoparticle vehicles as drug loading cargos. Additionally, novel techniques have been developed to address monotherapy resistance, including modulating biomarkers associated with TRAIL resistance in GBM cells. This review highlights the promising work to overcome the challenges of TRAIL-based therapies with the aim to facilitate improved TRAIL efficacy against GBM.", "journal": "Neuro-oncology advances", "publication_date": "2023-04-21", "doi": "10.1093/noajnl/vdad047", "authors": [ "Morrent Thang", "Clara Mellows", "Alison Mercer-Smith", "Phuong Nguyen", "Shawn Hingtgen" ], "keywords": [ "tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)", "TRAIL-sensitizing agents", "nanoparticle-mediated delivery", "glioblastoma", "gene and cell therapy" ] }, { "pmid": "38044611", "title": "[Advances in oncolytic virotherapy for glioma].", "abstract": "In recent years, there has been significant progress in the research of oncolytic viruses for the therapy of gliomas. The latest clinical trial results related to the modification, effectiveness, and safety of oncolytic viruses have brought hope for the development of glioblastoma treatments. Modified oncolytic viruses, particularly those based on the herpes simplex virus, have gained approval in Japan. Clinical trials involving recombinant poliovirus have shown better-than-expected survival outcomes with a strong safety profile. Notably, the first-time report of adenovirus in combination with immune checkpoint inhibitors for glioblastoma has demonstrated promising survival benefits and safety. However, challenges remain, including the selection of administration routes and the sustainability of treatment effects during oncolytic virus therapy. Therefore, further preclinical and clinical studies are required to improve the effectiveness and optimize treatment strategy for glioblastoma using oncolytic viruses.", "journal": "Zhonghua wai ke za zhi [Chinese journal of surgery]", "publication_date": "2023-12-01", "doi": "10.3760/cma.j.cn112139-20230908-00100", "authors": [ "G L Zhu", "S Wu", "J S Wu" ], "keywords": [] }, { "pmid": "35395355", "title": "Recent Advances in the Therapeutic Strategies of Glioblastoma Multiforme.", "abstract": "Glioblastoma multiforme (GBM) is one of the most common, most formidable, and deadliest malignant types of primary astrocytoma with a poor prognosis. At present, the standard of care includes surgical tumor resection, followed by radiation therapy concomitant with chemotherapy and temozolomide. New developments and significant advances in the treatment of GBM have been achieved in recent decades. However, despite the advances, recurrence is often inevitable, and the survival of patients remains low. Various factors contribute to the difficulty in identifying an effective therapeutic option, among which are tumor complexity, the presence of the blood-brain barrier (BBB), and the presence of GBM cancer stem cells, prompting the need for improving existing treatment approaches and investigating new treatment alternatives for ameliorating the treatment strategies of GBM. In this review, we outline some of the most recent literature on the various available treatment options such as surgery, radiotherapy, cytotoxic chemotherapy, gene therapy, immunotherapy, phototherapy, nanotherapy, and tumor treating fields in the treatment of GBM, and we list some of the potential future directions of GBM. The reviewed studies confirm that GBM is a sophisticated disease with several challenges for scientists to address. Hence, more studies and a multimodal therapeutic approach are crucial to yield an effective cure and prolong the survival of GBM patients.", "journal": "Neuroscience", "publication_date": "2022-04-06", "doi": "10.1016/j.neuroscience.2022.03.030", "authors": [ "Asraa Faris Aldoghachi", "Ahmed Faris Aldoghachi", "Koen Breyne", "King-Hwa Ling", "Pike-See Cheah" ], "keywords": [ "glioblastoma multiforme", "Immunotherapy", "chemotherapy", "radiotherapy", "Neoplastic Stem Cells", "immunotherapy", "cancer therapy", "Glioblastoma", "Humans", "Gene therapy", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "36765787", "title": "Exploring the Past, Present, and Future of Anti-Angiogenic Therapy in Glioblastoma.", "abstract": "Glioblastoma, a WHO grade IV astrocytoma, constitutes approximately half of malignant tumors of the central nervous system. Despite technological advancements and aggressive multimodal treatment, prognosis remains dismal. The highly vascularized nature of glioblastoma enables the tumor cells to grow and invade the surrounding tissue, and vascular endothelial growth factor-A (VEGF-A) is a critical mediator of this process. Therefore, over the past decade, angiogenesis, and more specifically, the VEGF signaling pathway, has emerged as a therapeutic target for glioblastoma therapy. This led to the FDA approval of bevacizumab, a monoclonal antibody designed against VEGF-A, for treatment of recurrent glioblastoma. Despite the promising preclinical data and its theoretical effectiveness, bevacizumab has failed to improve patients' overall survival. Furthermore, several other anti-angiogenic agents that target the VEGF signaling pathway have also not demonstrated survival improvement. This suggests the presence of other compensatory angiogenic signaling pathways that surpass the anti-angiogenic effects of these agents and facilitate vascularization despite ongoing VEGF signaling inhibition. Herein, we review the current state of anti-angiogenic agents, discuss potential mechanisms of anti-angiogenic resistance, and suggest potential avenues to increase the efficacy of this therapeutic approach.", "journal": "Cancers", "publication_date": "2023-01-29", "doi": "10.3390/cancers15030830", "authors": [ "Ashley B Zhang", "Khashayar Mozaffari", "Brian Aguirre", "Victor Li", "Rohan Kubba" ], "keywords": [ "tumor microenvironment", "angiogenesis", "glioblastoma" ] }, { "pmid": "36338705", "title": "Heterogeneity of glioblastoma stem cells in the context of the immune microenvironment and geospatial organization.", "abstract": "Glioblastoma (GBM) is an extremely aggressive and incurable primary brain tumor with a 10-year survival of just 0.71%. Cancer stem cells (CSCs) are thought to seed GBM's inevitable recurrence by evading standard of care treatment, which combines surgical resection, radiotherapy, and chemotherapy, contributing to this grim prognosis. Effective targeting of CSCs could result in insights into GBM treatment resistance and development of novel treatment paradigms. There is a major ongoing effort to characterize CSCs, understand their interactions with the tumor microenvironment, and identify ways to eliminate them. This review discusses the diversity of CSC lineages present in GBM and how this glioma stem cell (GSC) mosaicism drives global intratumoral heterogeneity constituted by complex and spatially distinct local microenvironments. We review how a tumor's diverse CSC populations orchestrate and interact with the environment, especially the immune landscape. We also discuss how to map this intricate GBM ecosystem through the lens of metabolism and immunology to find vulnerabilities and new ways to disrupt the equilibrium of the system to achieve improved disease outcome.", "journal": "Frontiers in oncology", "publication_date": "2022-10-19", "doi": "10.3389/fonc.2022.1022716", "authors": [ "Aryeh Silver", "Diana Feier", "Tanya Ghosh", "Maryam Rahman", "Jianping Huang" ], "keywords": [ "tumor microenvironment", "cancer stem cells", "cell interactions", "spatial profiling", "heterogeneity", "Glioblastoma", "immune landscape" ] }, { "pmid": "39399167", "title": "The transformative potential of mRNA vaccines for glioblastoma and human cancer: technological advances and translation to clinical trials.", "abstract": "Originally devised for cancer control, mRNA vaccines have risen to the forefront of medicine as effective instruments for control of infectious disease, notably their pivotal role in combating the COVID-19 pandemic. This review focuses on fundamental aspects of the development of mRNA vaccines, e.g., tumor antigens, vector design, and precise delivery methodologies, - highlighting key technological advances. The recent, promising success of personalized mRNA vaccines against pancreatic cancer and melanoma illustrates the potential value for other intractable, immunologically resistant, solid tumors, such as glioblastoma, as well as the potential for synergies with a combinatorial, immunotherapeutic approach. The impact and progress in human cancer, including pancreatic cancer, head and neck cancer, bladder cancer are reviewed, as are lessons learned from first-in-human CAR-T cell, DNA and dendritic cell vaccines targeting glioblastoma. Going forward, a roadmap is provided for the transformative potential of mRNA vaccines to advance cancer immunotherapy, with a particular focus on the opportunities and challenges of glioblastoma. The current landscape of glioblastoma immunotherapy and gene therapy is reviewed with an eye to combinatorial approaches harnessing RNA science. Preliminary preclinical and clinical data supports the concept that mRNA vaccines could be a viable, novel approach to prolong survival in patients with glioblastoma.", "journal": "Frontiers in oncology", "publication_date": "2024-09-27", "doi": "10.3389/fonc.2024.1454370", "authors": [ "Iulia Tapescu", "Peter J Madsen", "Pedro R Lowenstein", "Maria G Castro", "Stephen J Bagley" ], "keywords": [ "glioma", "immuno-oncology", "vaccine", "clinical trial", "glioblastoma", "mRNA", "brain tumor", "immunotherapy" ] }, { "pmid": "33640445", "title": "Cancer cell heterogeneity & plasticity in glioblastoma and brain tumors.", "abstract": "Brain tumors remain one of the most difficult tumors to treat and, depending on the diagnosis, have a poor prognosis. Of brain tumors, glioblastoma (GBM) is the most common malignant glioma and has a dismal prognosis, with only about 5% of patients alive five years after diagnosis. While advances in targeted therapies and immunotherapies are rapidly improving outcomes in a variety of other cancers, the standard of care for GBM has largely remained unaltered since 2005. There are many well-studied challenges that are either unique to brain tumors (i.e., blood-brain barrier and immunosuppressive environment) or amplified within GBM (i.e., tumor heterogeneity at the cellular and molecular levels, plasticity, and cancer stem cells) that make this disease particularly difficult to treat. While we touch on all these concepts, the focus of this review is to discuss the immense inter- and intra-tumoral heterogeneity and advances in our understanding of tumor cell plasticity and epigenetics in GBM. With each improvement in technology, our understanding of the complexity of tumoral heterogeneity and plasticity improves and we gain more clarity on the causes underlying previous therapeutic failures. However, these advances are unlocking new therapeutic opportunities that scientists and physicians are currently exploiting and have the potential for new breakthroughs.", "journal": "Seminars in cancer biology", "publication_date": "2021-02-25", "doi": "10.1016/j.semcancer.2021.02.014", "authors": [ "Adam Lauko", "Alice Lo", "Manmeet S Ahluwalia", "Justin D Lathia" ], "keywords": [ "Heterogeneity", "Neoplastic Stem Cells", "Plasticity", "Epigenetics", "Tumor microenvironment", "Glioblastoma", "Humans", "Glioma", "Brain Neoplasms", "Cell Plasticity" ] }, { "pmid": "39766048", "title": "Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment: A Systematic Review.", "abstract": "PURPOSE: A glioblastoma (GBM) is a primary brain tumor with significant unmet therapeutic needs. Immune checkpoint inhibitors (ICIs) have marked therapeutic benefits in many different cancers but have yet to show benefit for most GBM patients in phase III trials. METHODS: A systematic review querying ClinicalTrials.gov for prospective clinical trials investigating ICI in GBM between 1950 and July 2024 was performed. Search terms comprised 11 distinct ICIs. Data abstracted include clinical trial NCT numbers with study titles and status, enrollment information, interventions, and more. Clinical trial identifying information, interventions, and outcomes were extracted. RESULTS: One hundred and seventeen clinical trials were identified; four were phase 3. Most involved PD-1 or CTLA-4 blockade as monotherapy or in combination with standard-of-care. The large, randomized trials included CHECKMATE 143, CHECKMATE 498, CHECKMATE 548, and NRG BN007. These showed no improvement in median overall survival or progression-free survival in unselected patients. Biomarker-directed analyses suggest that a subset of GBM patients may benefit. CONCLUSIONS: ICI for the treatment of GBM has not demonstrated clear evidence of efficacy thus far. This review serves as a quick reference of ICI trial results in GBM. Biomarker-driven patient selection and/or novel approaches to overcome resistance mechanisms remain areas of viable inquiry.", "journal": "Cancers", "publication_date": "2024-12-12", "doi": "10.3390/cancers16244148", "authors": [ "Archit Bharathwaj Baskaran", "Olivia A Kozel", "Omkar Venkatesh", "Derek A Wainwright", "Adam M Sonabend" ], "keywords": [ "glioblastoma", "PD1", "PD-L1", "CTLA4", "immune checkpoint inhibition", "LAG3", "PD-L2" ] }, { "pmid": "33148506", "title": "Pre-clinical tumor models of primary brain tumors: Challenges and opportunities.", "abstract": "Primary brain tumors are a heterogeneous group of malignancies that originate in cells of the central nervous system. A variety of models tractable for preclinical studies have been developed to recapitulate human brain tumors, allowing us to understand the underlying pathobiology and explore potential treatments. However, many promising therapeutic strategies identified using preclinical models have shown limited efficacy or failed at the clinical trial stage. The inability to develop therapeutic strategies that significantly improve survival rates in patients highlight the compelling need to revisit the design of currently available animal models and explore the use of new models that allow us to bridge the gap between promising preclinical findings and clinical translation. In this review, we discuss current strategies used to model glioblastoma, the most malignant brain tumor in adults and highlight the shortcomings of specific models that must be circumvented for the development of innovative therapeutic strategies.", "journal": "Biochimica et biophysica acta. Reviews on cancer", "publication_date": "2020-10-23", "doi": "10.1016/j.bbcan.2020.188458", "authors": [ "Farhana Akter", "Brennan Simon", "Nadine Leonie de Boer", "Navid Redjal", "Hiroaki Wakimoto" ], "keywords": [ "Animals", "Adult", "Survival Rate", "Brain tumor model", "Therapeutic development", "Glioblastoma", "Survival Analysis", "Humans", "Disease Models, Animal", "Neurooncology", "Glioma", "Brain Neoplasms" ] }, { "pmid": "36311702", "title": "Targeting tumor-associated macrophages for the immunotherapy of glioblastoma: Navigating the clinical and translational landscape.", "abstract": "Tumor-associated macrophages (TAMs) can directly clear tumor cells and enhance the phagocytic ability of immune cells. An abundance of TAMs at the site of the glioblastoma tumor indicates that TAM-targeting immunotherapy could represent a potential form of treatment for this aggressive cancer. Herein, we discuss: i) the dynamic role of TAMs in glioblastoma; ii) describe the formation of the immunosuppressive tumor microenvironment; iii) summarize the latest clinical trial data that reveal how TAM function can be regulated in favor tumor eradication; and lastly, iv) evaluate the implications of existing and novel translational approaches for treating glioblastoma in clinical practice.", "journal": "Frontiers in immunology", "publication_date": "2022-10-13", "doi": "10.3389/fimmu.2022.1024921", "authors": [ "Zide Wang", "Hanlin Zhong", "Xiaohong Liang", "Shilei Ni" ], "keywords": [ "tumor-associated macrophage", "tumor microenvironment", "Immunotherapy", "Macrophages", "Tumor-Associated Macrophages", "glioblastoma", "immunotherapy", "Glioblastoma", "Tumor Microenvironment", "Humans", "immunosuppression" ] }, { "pmid": "39123366", "title": "Glioblastoma Standard of Care: Effects on Tumor Evolution and Reverse Translation in Preclinical Models.", "abstract": "Glioblastoma (GBM) presents a significant public health challenge as the deadliest and most common malignant brain tumor in adults. Despite standard-of-care treatment, which includes surgery, radiation, and chemotherapy, mortality rates are high, underscoring the critical need for advancing GBM therapy. Over the past two decades, numerous clinical trials have been performed, yet only a small fraction demonstrated a benefit, raising concerns about the predictability of current preclinical models. Traditionally, preclinical studies utilize treatment-naïve tumors, failing to model the clinical scenario where patients undergo standard-of-care treatment prior to recurrence. Recurrent GBM generally exhibits distinct molecular alterations influenced by treatment selection pressures. In this review, we discuss the impact of treatment-surgery, radiation, and chemotherapy-on GBM. We also provide a summary of treatments used in preclinical models, advocating for their integration to enhance the translation of novel strategies to improve therapeutic outcomes in GBM.", "journal": "Cancers", "publication_date": "2024-07-24", "doi": "10.3390/cancers16152638", "authors": [ "Louis T Rodgers", "John L Villano", "Anika M S Hartz", "Björn Bauer" ], "keywords": [ "recurrent tumor", "radiation therapy", "resection", "glioblastoma", "reverse translation", "temozolomide", "preclinical models", "standard of care" ] }, { "pmid": "34371744", "title": "Glioblastoma Multiforme-A Look at the Past and a Glance at the Future.", "abstract": "Gliomas are the most common type of brain tumor that occur in adults and children. Glioblastoma multiforme (GBM) is the most common, aggressive form of brain cancer in adults and is universally fatal. The current standard-of-care options for GBM include surgical resection, radiotherapy, and concomitant and/or adjuvant chemotherapy. One of the major challenges that impedes success of chemotherapy is the presence of the blood-brain barrier (BBB). Because of the tightly regulated BBB, immune surveillance in the central nervous system (CNS) is poor, contributing to unregulated glioma cell growth. This review gives a comprehensive overview of the latest advances in treatment of GBM with emphasis on the significant advances in immunotherapy and novel therapeutic delivery strategies to enhance treatment for GBM.", "journal": "Pharmaceutics", "publication_date": "2021-07-09", "doi": "10.3390/pharmaceutics13071053", "authors": [ "Jasmine L King", "Soumya Rahima Benhabbour" ], "keywords": [ "blood–brain barrier (BBB)", "chemotherapy", "blood–brain tumor barrier (BBTB)", "stem cell-based therapy", "glioblastoma", "immune checkpoint inhibitors (ICIs)", "focused ultrasound (FUS)", "radiation", "surgery", "hydrogels", "smart hydrogels", "stem cell engineering" ] }, { "pmid": "33432111", "title": "The role of E3 ubiquitin ligases in the development and progression of glioblastoma.", "abstract": "Despite recent advances in our understanding of the disease, glioblastoma (GB) continues to have limited treatment options and carries a dismal prognosis for patients. Efforts to stratify this heterogeneous malignancy using molecular classifiers identified frequent alterations in targetable proteins belonging to several pathways including the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signalling pathways. However, these findings have failed to improve clinical outcomes for patients. In almost all cases, GB becomes refractory to standard-of-care therapy, and recent evidence suggests that disease recurrence may be associated with a subpopulation of cells known as glioma stem cells (GSCs). Therefore, there remains a significant unmet need for novel therapeutic strategies. E3 ubiquitin ligases are a family of >700 proteins that conjugate ubiquitin to target proteins, resulting in an array of cellular responses, including DNA repair, pro-survival signalling and protein degradation. Ubiquitin modifications on target proteins are diverse, ranging from mono-ubiquitination through to the formation of polyubiquitin chains and mixed chains. The specificity in substrate tagging and chain elongation is dictated by E3 ubiquitin ligases, which have essential regulatory roles in multiple aspects of brain cancer pathogenesis. In this review, we begin by briefly summarising the histological and molecular classification of GB. We comprehensively describe the roles of E3 ubiquitin ligases in RTK and MAPK, as well as other, commonly altered, oncogenic and tumour suppressive signalling pathways in GB. We also describe the role of E3 ligases in maintaining glioma stem cell populations and their function in promoting resistance to ionizing radiation (IR) and chemotherapy. Finally, we consider how our knowledge of E3 ligase biology may be used for future therapeutic interventions in GB, including the use of blood-brain barrier permeable proteolysis targeting chimeras (PROTACs).", "journal": "Cell death and differentiation", "publication_date": "2021-01-11", "doi": "10.1038/s41418-020-00696-6", "authors": [ "Luke M Humphreys", "Paul Smith", "Zhuoyao Chen", "Shahd Fouad", "Vincenzo D'Angiolella" ], "keywords": [ "Ubiquitination", "Animals", "Proteolysis", "Ubiquitin-Protein Ligases", "Signal Transduction", "Protein Binding", "Polyubiquitin", "Glioblastoma", "Humans", "Brain Neoplasms", "Antineoplastic Agents" ] }, { "pmid": "35662275", "title": "Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them.", "abstract": "Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood-brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration.", "journal": "British journal of cancer", "publication_date": "2022-06-04", "doi": "10.1038/s41416-022-01864-w", "authors": [ "Karl John Habashy", "Rana Mansour", "Charbel Moussalem", "Raymond Sawaya", "Michel J Massaad" ], "keywords": [ "Immunotherapy", "Immunologic Factors", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "36724255", "title": "Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.", "abstract": "Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a \"hot\" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2023-02-01", "doi": "10.1073/pnas.2219199120", "authors": [ "Meenal Datta", "Sampurna Chatterjee", "Elizabeth M Perez", "Simon Gritsch", "Sylvie Roberge" ], "keywords": [ "biomarkers", "tumor microenvironment", "Animals", "Mice", "immune checkpoint blockers", "glioblastoma", "immune-related adverse events", "CD8-Positive T-Lymphocytes", "Immune Checkpoint Inhibitors", "Losartan", "Glioblastoma", "Tumor Microenvironment", "Edema" ] }, { "pmid": "38053701", "title": "Tumor treating fields for the treatment of glioblastoma: Current understanding and future perspectives.", "abstract": "BACKGROUND: This review focuses on the recently published evidence on tumor treating fields (TTFields) administered alone or in combination with locoregional and systemic options for treating glioblastoma (GBM) in the past ten years. The aim is to critically summarize the novelty and results obtained with this innovative tool, which is becoming part of the armamentarium of neurosurgeons and neuro-oncologists. METHODS: A comprehensive search and analysis were conducted on pivotal studies published in the past ten years. Furthermore, all completed clinical trials, whose results were published on clinicaltrials.gov, were examined and included in the present review, encompassing both recurrent (r) and newly diagnosed (n) GBM. Finally, an additional examination of the ongoing clinical trials was also conducted. RESULTS: Recent trials have shown promising results both in patients with nGBM and rGBM/progressive (rGBM), leading to Food and Drug Administration approval in selected patients and the Congress of Neurological Surgeons to include TTFields into current guidelines on the management of GBM (P100034/S001-029). Recently, different randomized trials have demonstrated promising results of TTFields in combination with standard treatment of n- and rGBM, especially when considering progression-free and overall survival, maintaining a low rate of mild to moderate adverse events. CONCLUSION: Optimal outcomes were obtained in nGBM and progressive disease. A possible future refinement of TTFields could significantly impact the treatment of rGBM and the actual standard of care for GBM, given the better safety profile and survival effects.", "journal": "Surgical neurology international", "publication_date": "2023-11-10", "doi": "10.25259/SNI_674_2023", "authors": [ "Antonio Colamaria", "Augusto Leone", "Nicola Pio Fochi", "Veronica Di Napoli", "Guido Giordano" ], "keywords": [ "Tumor treating fields", "High-grade glioma", "Clinical trial", "Glioblastoma", "Brain tumor" ] }, { "pmid": "39231832", "title": "Interleukin 6 and cancer resistance in glioblastoma multiforme.", "abstract": "Despite unprecedented survival in patients with glioblastoma (GB), the aggressive primary brain cancer remains largely incurable and its mechanisms of treatment resistance have gained particular attention. The cytokine interleukin 6 (IL-6) and its receptor weave through the hallmarks of malignant gliomas and may represent a key vulnerability to GB. Known for activating the STAT3 pathway in autocrine fashion, IL-6 is amplified in GB and has been recognized as a negative biomarker for GB prognosis, rendering it a putative target of novel GB therapies. While it has been recognized as a biologically active component of GB for three decades only with concurrent advances in understanding of complementary immunotherapy has the concept of targeting IL-6 for a human clinical trial gained scientific footing.", "journal": "Neurosurgical review", "publication_date": "2024-09-05", "doi": "10.1007/s10143-024-02783-5", "authors": [ "Donald Detchou", "Umaru Barrie" ], "keywords": [ "STAT3", "Immunotherapy", "Interleukin-6", "Receptors, Interleukin-6", "Interleukin 6", "STAT3 Transcription Factor", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "Brain Neoplasms", "Tocilizumab" ] }, { "pmid": "33902757", "title": "Drug target ranking for glioblastoma multiforme.", "abstract": "BACKGROUND: Glioblastoma Multiforme, an aggressive primary brain tumor, has a poor prognosis and no effective standard of care treatments. Most patients undergoing radiotherapy, along with Temozolomide chemotherapy, develop resistance to the drug, and recurrence of the tumor is a common issue after the treatment. We propose to model the pathways active in Glioblastoma using Boolean network techniques. The network captures the genetic interactions and possible mutations that are involved in the development of the brain tumor. The model is used to predict the theoretical efficacies of drugs for the treatment of cancer. RESULTS: We use the Boolean network to rank the critical intervention points in the pathway to predict an effective therapeutic strategy for Glioblastoma. Drug repurposing helps to identify non-cancer drugs that could be effective in cancer treatment. We predict the effectiveness of drug combinations of anti-cancer and non-cancer drugs for Glioblastoma. CONCLUSIONS: Given the genetic profile of a GBM tumor, the Boolean model can predict the most effective targets for treatment. We also identified two-drug combinations that could be more effective in killing GBM cells than conventional chemotherapeutic agents. The non-cancer drug Aspirin could potentially increase the cytotoxicity of TMZ in GBM patients.", "journal": "BMC biomedical engineering", "publication_date": "2021-04-26", "doi": "10.1186/s42490-021-00052-w", "authors": [ "Radhika Saraf", "Shaghayegh Agah", "Aniruddha Datta", "Xiaoqian Jiang" ], "keywords": [ "Drug resistance", "Drug repurposing", "Cancer", "Glioblastoma", "Drug target ranking", "Boolean network modeling" ] }, { "pmid": "33710606", "title": "Trends in glioblastoma treatment research: an analysis of clinical trials and literature.", "abstract": "INTRODUCTION: Glioblastoma is the most common, and the most lethal, primary malignant brain tumour in adults. The aim of the study was to present a comprehensive, data-based review of glioblastoma treatment research, considering all clinical trials and peer-reviewed journal publications. MATERIALS AND METHODS: Data regarding all glioblastoma clinical trials that was available on 7 August 2019 on ClinicalTrials.gov was analysed. Information on interventions' mechanisms of action was obtained from AdisInsight. A PubMed search for 'glioblastoma' was performed in September 2019. Citation counts were gathered from Scopus. Custom software for obtaining and analyzing data was developed by the authors. RESULTS: 1,388 clinical trials on glioblastoma with a start date between 1979 and 2020 were identified. The distribution of glioblastoma clinical trial phases differs significantly from that of other high-mortality cancers. 526 unique interventions of clinical trials and 206 molecular targets have been isolated. 32,410 publications on glioblastoma have been found, the number having increased especially since 2006. Publications on identified treatment options comprised 32.2%. Publications on glioblastoma are cited on average 4.27 times per year. The average specificity of treatment options' publications for glioblastoma is 6.9%. CONCLUSIONS: Glioblastoma treatment options and their molecular targets can be quantitatively ranked according to their scientific research output. To the best of our knowledge, no such registries have been elaborated before.", "journal": "Neurologia i neurochirurgia polska", "publication_date": "2021-03-12", "doi": "10.5603/PJNNS.a2021.0024", "authors": [ "Aleksander E Łaba", "Piotr Ziółkowski" ], "keywords": [ "Bibliometrics", "research", "clinical trial", "treatment", "glioblastoma", "review", "Registries", "Glioblastoma", "Humans", "literature", "Brain Neoplasms" ] }, { "pmid": "34466804", "title": "Mouse models of glioblastoma for the evaluation of novel therapeutic strategies.", "abstract": "Glioblastoma (GBM) is an incurable brain tumor with a median survival of approximately 15 months despite an aggressive standard of care that includes surgery, chemotherapy, and ionizing radiation. Mouse models have advanced our understanding of GBM biology and the development of novel therapeutic strategies for GBM patients. However, model selection is crucial when testing developmental therapeutics, and each mouse model of GBM has unique advantages and disadvantages that can influence the validity and translatability of experimental results. To shed light on this process, we discuss the strengths and limitations of 3 types of mouse GBM models in this review: syngeneic models, genetically engineered mouse models, and xenograft models, including traditional xenograft cell lines and patient-derived xenograft models.", "journal": "Neuro-oncology advances", "publication_date": "2021-07-26", "doi": "10.1093/noajnl/vdab100", "authors": [ "Alexander F Haddad", "Jacob S Young", "Dominic Amara", "Mitchel S Berger", "David R Raleigh" ], "keywords": [ "U87", "tumor", "glioblastoma", "GL261", "murine models" ] }, { "pmid": "35716200", "title": "Management of newly diagnosed glioblastoma multiforme: current state of the art and emerging therapeutic approaches.", "abstract": "Glioblastoma multiforme represent > 50% of primary gliomas and have five year survival rates of ~ 5%. Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide remains the standard treatment since published by Stupp et al. (in N Engl J Med 352:987-996, 2005), with additional benefit for patients with MGMT-methylated tumors. We review the current treatment landscape and ongoing efforts to improve these outcomes. An extensive literature search of Pubmed and Google Scholar involving the search terms \"glioblastoma,\" \"glioblastoma multiforme,\" or \"GBM\" for papers published to July 2021 was conducted and papers evaluated for relevance. As well as current data that informs clinical practice, we review ongoing clinical research in both newly diagnosed and recurrent settings that provides hope for a breakthrough. The Stupp protocol remains standard of care in 2021. Addition of tumor treating fields improved mOS modestly, with benefit seen in MGMT-methylated and unmethylated cohorts and also improved time to cognitive decline but has not been widely adopted. The addition of lomustine to temozolomide, in MGMT-methylated patients, also showed a mOS benefit but further investigation is required. Other promising therapeutic strategies including anti-angiogenic therapy, targeted therapy, and immunotherapy have yet to show a survival advantage. Improvements in the multidisciplinary management, surgical techniques and equipment, early palliative care, carrier support, and psychological support may be responsible for improving survival over time. Despite promising preclinical rationale, immunotherapy and targeted therapy are struggling to impact survival. A number of ongoing clinical trials provide hope for a breakthrough.", "journal": "Medical oncology (Northwood, London, England)", "publication_date": "2022-06-18", "doi": "10.1007/s12032-022-01708-w", "authors": [ "D J McMahon", "J P Gleeson", "S O'Reilly", "R M Bambury" ], "keywords": [ "Tumor treating fields", "Lomustine", "Immunotherapy", "Antineoplastic Agents, Alkylating", "Glioblastoma multiforme", "GBM", "NEON-D-21–00968", "Astrocytoma", "Glioblastoma", "Humans", "Supportive care", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "36445396", "title": "Assessment and prediction of glioblastoma therapy response: challenges and opportunities.", "abstract": "Glioblastoma is the most aggressive type of primary adult brain tumour. The median survival of patients with glioblastoma remains approximately 15 months, and the 5-year survival rate is <10%. Current treatment options are limited, and the standard of care has remained relatively constant since 2011. Over the last decade, a range of different treatment regimens have been investigated with very limited success. Tumour recurrence is almost inevitable with the current treatment strategies, as glioblastoma tumours are highly heterogeneous and invasive. Additionally, another challenging issue facing patients with glioblastoma is how to distinguish between tumour progression and treatment effects, especially when relying on routine diagnostic imaging techniques in the clinic. The specificity of routine imaging for identifying tumour progression early or in a timely manner is poor due to the appearance similarity of post-treatment effects. Here, we concisely describe the current status and challenges in the assessment and early prediction of therapy response and the early detection of tumour progression or recurrence. We also summarize and discuss studies of advanced approaches such as quantitative imaging, liquid biomarker discovery and machine intelligence that hold exceptional potential to aid in the therapy monitoring of this malignancy and early prediction of therapy response, which may decisively transform the conventional detection methods in the era of precision medicine.", "journal": "Brain : a journal of neurology", "publication_date": "2023-04", "doi": "10.1093/brain/awac450", "authors": [ "Dan Qi", "Jing Li", "C Chad Quarles", "Ekokobe Fonkem", "Erxi Wu" ], "keywords": [ "liquid biomarker", "machine learning", "multiparametric imaging", "glioblastoma", "Disease Progression", "Clinical Decision Rules", "Glioblastoma", "Machine Learning", "Humans", "Biomarkers", "therapy response" ] }, { "pmid": "41385182", "title": "VAL-083 is effective in patients with newly-diagnosed MGMT-unmethylated glioblastoma: report of phase II study.", "abstract": "PURPOSE: Unmethylated MGMT is a validated biomarker for temozolomide (TMZ) resistance and poor prognosis in glioblastoma. VAL-083 (dianhydrogalactitol; DAG) is a DNA-targeting agent that forms interstrand crosslinks at O6/N7-guanine, inducing double-strand breaks and cell death independently of MGMT-mediated DNA repair. This study aimed to evaluate whether first-line VAL-083 combined with radiotherapy improves efficacy compared to standard-of-care TMZ plus radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. METHODS: VAL-083 was administered intravenously on days 1-3 of a 21-day cycle, starting on day 1 of radiotherapy, with a second 3-day cycle on days 22-24 of radiotherapy. After completing the 6-week radiotherapy regimen, patients began adjuvant maintenance therapy with VAL-083 alone, administered IV at the same dose and regimen (Cycles 3-10), for up to 8 maintenance cycles. RESULTS: At the censor date, the median overall survival (OS) across all patients from the start of VAL-083 treatment was 19.2 months across all dose levels. Survival probabilities from VAL-083 were 93.0%, 68.7%, 51.2%, and 28.4% at 6, 12, 18, and 24 months, respectively. For patients receiving 30 mg/m2/day VAL-083, 15/25 (60%) had died by the censor date, with a median survival of 18.0 months. Pharmacokinetics exhibited dose-linearity. CSF levels at 2 h post-infusion were comparable to or exceeded plasma levels. Common adverse events included thrombocytopenia and neutropenia. CONCLUSIONS: VAL-083 (30 mg/m2/day) combined with radiation therapy was generally safe and well tolerated. Adverse events aligned with previous studies. This regimen, compared to standard-of-care TMZ, showed potential benefits in terms of disease progression and overall survival. Trial registration ClinicalTrials.gov ID NCT03050736, dated: February 13, 2017.", "journal": "Discover oncology", "publication_date": "2025-12-12", "doi": "10.1007/s12672-025-04235-y", "authors": [ "Chengcheng Guo", "Qunying Yang", "Meiling Deng", "Xiaoling Qiu", "Shaoxiong Wu" ], "keywords": [ "Radiation", "Glioblastoma", "MGMT-unmethylated", "Newly-diagnose", "VAL-083" ] }, { "pmid": "37494539", "title": "Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial.", "abstract": "PURPOSE: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma. EXPERIMENTAL DESIGN: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival. RESULTS: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment. CONCLUSIONS: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "publication_date": "2023-10", "doi": "10.1158/1078-0432.CCR-23-0926", "authors": [ "Tobias Kessler", "Daniel Schrimpf", "Laura Doerner", "Ling Hai", "Leon D Kaulen" ], "keywords": [ "High-Throughput Nucleotide Sequencing", "Lomustine", "DNA Repair Enzymes", "O(6)-Methylguanine-DNA Methyltransferase", "DNA Modification Methylases", "Prognosis", "Glioblastoma", "Biomarkers", "Humans", "DNA Methylation", "Brain Neoplasms", "Bevacizumab" ] }, { "pmid": "40913573", "title": "Temozolomide-Derived Therapeutic Strategies to Overcome Resistance in Glioblastoma.", "abstract": "Glioblastoma multiforme (GBM) accounts for nearly half of malignant CNS tumors and has a dismal 5-year survival rate of 5.5%. The current standard of care comprises maximal surgical resection, followed by radiotherapy with concurrent temozolomide (TMZ) and subsequent adjuvant TMZ chemotherapy. While TMZ modestly extends survival, its efficacy is limited in patients with unmethylated MGMT promoters, representing over 50% of GBM cases. To improve TMZ's clinical performance, research has focused on structural modifications, TMZ-based hybrids and conjugates, nanoformulations, and rational combination therapies. This perspective summarizes medicinal chemistry approaches to optimize TMZ derivatives to overcome resistance in GBM. We also highlight clinical trial outcomes of TMZ-based combinatorial regimens. Continued advances in TMZ-derived drug development, together with emerging therapeutics such as immunotherapies and oncolytic virotherapies, hold considerable promise for improving treatment outcomes in GBM.", "journal": "Journal of medicinal chemistry", "publication_date": "2025-09-06", "doi": "10.1021/acs.jmedchem.5c02019", "authors": [ "Hualin Zhang", "Yupeng Li" ], "keywords": [ "Animals", "Antineoplastic Agents, Alkylating", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "35700581", "title": "Dendritic cell vaccines for glioblastoma fail to complete clinical translation: Bottlenecks and potential countermeasures.", "abstract": "Glioblastoma (GBM) is a heterogeneous and invasive WHO grade IV brain tumor. Patients with GBM have a median overall survival (OS) of only 14 to 17 months when treated with surgical resection and chemoradiation. As one of the most promising anti-tumor immunotherapies, dendritic cell (DC) vaccines have demonstrated good efficacy, safety, and tolerability in many clinical trials. However, to date, no Phase III clinical trial has achieved positive endpoints and truly implement clinical development and transformation. Moreover, the survival benefits of DC vaccines for patients with GBM seem to have a delayed effect; therefore, we urgently require strategies to optimize DC vaccines to advance the time point of its survival benefits. Here, we discuss the latest clinical trial progress of DC vaccines in GBM and summarize the benefits and drawbacks of various vaccine design options, as well as the challenges faced in clinical translation. Moreover, we target future combination therapy strategies for DC vaccines in GBM, which provides a new perspective for comprehensively understanding the effectiveness, limitations, and new directions of the development of DC vaccines.", "journal": "International immunopharmacology", "publication_date": "2022-06-11", "doi": "10.1016/j.intimp.2022.108929", "authors": [ "Luohong Li", "Jing Zhou", "Xueting Dong", "Qianjin Liao", "Dongbo Zhou" ], "keywords": [ "Limitations", "Immunotherapy", "Dendritic cell vaccine", "Cancer Vaccines", "Combination therapy", "Glioblastoma", "Humans", "Clinical translation", "Dendritic Cells", "Brain Neoplasms" ] }, { "pmid": "38542190", "title": "A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance.", "abstract": "A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.", "journal": "International journal of molecular sciences", "publication_date": "2024-03-12", "doi": "10.3390/ijms25063217", "authors": [ "Aniruddha S Karve", "Janki M Desai", "Sidharth N Gadgil", "Nimita Dave", "Trisha M Wise-Draper" ], "keywords": [ "Antineoplastic Agents, Alkylating", "Quality of Life", "combination therapeutics", "glioblastoma", "DNA", "treatment resistance", "Glioblastoma", "Drug Resistance, Neoplasm", "Humans", "Cell Line, Tumor", "Neoplasm Recurrence, Local", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "35047971", "title": "Local Delivery and Glioblastoma: Why Not Combining Sustained Release and Targeting?", "abstract": "Glioblastoma is one of the most aggressive brain tumors and is associated with a very low overall median survival despite the current treatment. The standard of care used in clinic is the Stupp's protocol which consists of a maximal resection of the tumor when possible, followed by radio and chemotherapy using temozolomide. However, in most cases, glioblastoma cells infiltrate healthy tissues and lead to fatal recurrences. There are a lot of hurdles to overcome in the development of new therapeutic strategies such as tumor heterogeneity, cell infiltration, alkylating agent resistance, physiological barriers, etc., and few treatments are on the market today. One of them is particularly appealing because it is a local therapy, which does not bring additional invasiveness since tumor resection is included in the gold standard treatment. They are implants: the Gliadel® wafers, which are deposited post-surgery. Nevertheless, in addition to presenting important undesirable effects, it does not bring any major benefit in the therapy despite the strategy being particularly attractive. The purpose of this review is to provide an overview of recent advances in the development of innovative therapeutic strategies for glioblastoma using an implant-type approach. The combination of this local strategy with effective targeting of the tumor microenvironment as a whole, also developed in this review, may be of interest to alleviate some of the obstacles encountered in the treatment of glioblastoma.", "journal": "Frontiers in medical technology", "publication_date": "2021-11-22", "doi": "10.3389/fmedt.2021.791596", "authors": [ "Claire Gazaille", "Marion Sicot", "Patrick Saulnier", "Joël Eyer", "Guillaume Bastiat" ], "keywords": [ "nanoparticle-loaded hydrogel", "local delivery", "glioblastoma", "Gliadel® wafers", "targeting" ] }, { "pmid": "37289203", "title": "Dendritic cell vaccine trials in gliomas: Untangling the lines.", "abstract": "Glioblastoma is a deadly brain tumor without any significantly successful treatments to date. Tumor antigen-targeted immunotherapy platforms including peptide and dendritic cell (DC) vaccines, have extended survival in hematologic malignancies. The relatively \"cold\" tumor immune microenvironment and heterogenous nature of glioblastoma have proven to be major limitations to translational application and efficacy of DC vaccines. Furthermore, many DC vaccine trials in glioblastoma are difficult to interpret due to a lack of contemporaneous controls, absence of any control comparison, or inconsistent patient populations. Here we review glioblastoma immunobiology aspects that are relevant to DC vaccines, review the clinical experience with DC vaccines targeting glioblastoma, discuss challenges in clinical trial design, and summarize conclusions and directions for future research for the development of effective DC vaccines for patients.", "journal": "Neuro-oncology", "publication_date": "2023-10", "doi": "10.1093/neuonc/noad088", "authors": [ "Kelly M Hotchkiss", "Kristen A Batich", "Aditya Mohan", "Rifaquat Rahman", "Steven Piantadosi" ], "keywords": [ "control arm", "patient selection", "Immunotherapy", "glioblastoma", "Clinical trial", "dc vaccine", "Cancer Vaccines", "Glioblastoma", "Tumor Microenvironment", "Humans", "Dendritic Cells", "Glioma", "Brain Neoplasms" ] }, { "pmid": "40642066", "title": "Rational therapeutic targeting of myeloid cells in glioblastoma: challenges and perspectives.", "abstract": "Glioblastoma (GB) is the most aggressive tumor of the central nervous system (CNS), accounting for almost 80% of all primary brain tumors. Despite standard-of-care consisting of surgical resection, when possible, adjuvant radiotherapy (RT) and chemotherapy with Temozolomide (TMZ), GB remains highly fatal, with an estimated recurrence rate of over 90% and a median overall survival (OS) of around 15 months from diagnosis. Several factors contribute to such poor patient outcome, including a unique myeloid-rich tumor microenvironment (TME) that confers immunosuppression and therapeutic resistance. Multi-omics, single-cell transcriptomics and multi-modal spatial analyses of GB are unraveling the diversity of brain myeloid cells, including activated microglia, border-associated macrophages (BAM), and monocyte-derived glioma-associated macrophages (GAM), instructed by ontogeny, spatial distribution, cell-cell interactions and response to metabolic cues in the TME. In this review, we elaborate on the heterogeneity and plasticity of myeloid cells in GB and discuss the promise and challenges for rational therapeutic targeting of GAMs in GB.", "journal": "Frontiers in immunology", "publication_date": "2025-06-26", "doi": "10.3389/fimmu.2025.1472710", "authors": [ "Faruk Akay", "Maya Saleh" ], "keywords": [ "tumor microenvironment", "innate immunity", "Animals", "Tumor-Associated Macrophages", "glioblastoma", "clinical trials", "immunotherapy", "central nervous system", "Myeloid Cells", "Glioblastoma", "Tumor Microenvironment", "Humans", "glioma-associated macrophages", "myeloid cells", "Brain Neoplasms" ] }, { "pmid": "39099691", "title": "Current chemotherapy strategies for adults with IDH-wildtype glioblastoma.", "abstract": "INTRODUCTION: Glioblastoma, despite advancements in molecular evolution, remains incurable and has low survival rates. Currently, two of the most commonly used chemotherapy regimens are temozolomide and CCNU. This review aims to provide a comprehensive analysis of the current status of chemotherapy strategies for GBM. METHODS: We reviewed the published literature describing the chemotherapy regimen differences in system treatment of GBM reported in the last ten years and summarised the available information that may reveal the latest changes in chemotherapy. RESULTS: In patients with adequate functioning, temozolomide and radiation are the primary treatments for newly diagnosed GBM. We recommend postoperative radiation therapy with concurrent and adjuvant temozolomide for patients with MGMT-methylated GBM who are less than 70 years old. Combining temozolomide and lomustine with radiation therapy may be an option for younger, fit patients, but efficacy data is inconclusive. For patients with unknown MGMT methylation status, radiation therapy combined with temozolomide remains the standard of care. We recommend hypofractionated radiation and concurrent temozolomide treatment for elderly patients over 70 years old who have satisfactory performance and no significant underlying health conditions. We should tailor treatment choices to each patient's personal preferences, previous treatments, function, quality of life, and overall care objectives. CONCLUSION: Radiation therapy, along with temozolomide, is still the standard of care for most people with MGMT-unmethylated GBMs because there aren't any better options, and it's generally safe and well-tolerated. These patients have a lower overall survival rate and less benefit from temozolomide, but there are no better alternatives. Clinical trial participation is encouraged.", "journal": "Frontiers in oncology", "publication_date": "2024-07-19", "doi": "10.3389/fonc.2024.1438905", "authors": [ "Jing Bao", "Rui Sun", "Zhenjiang Pan", "Shepeng Wei" ], "keywords": [ "chemotherapy", "MGMT", "glioblastoma", "temozolomide", "lomustine" ] }, { "pmid": "37402043", "title": "The Future Glioblastoma Clinical Trials Landscape: Early Phase 0, Window of Opportunity, and Adaptive Phase I-III Studies.", "abstract": "PURPOSE OF REVIEW: Innovative clinical trial designs for glioblastoma (GBM) are needed to expedite drug discovery. Phase 0, window of opportunity, and adaptive designs have been proposed, but their advanced methodologies and underlying biostatistics are not widely known. This review summarizes phase 0, window of opportunity, and adaptive phase I-III clinical trial designs in GBM tailored to physicians. RECENT FINDINGS: Phase 0, window of opportunity, and adaptive trials are now being implemented for GBM. These trials can remove ineffective therapies earlier during drug development and improve trial efficiency. There are two ongoing adaptive platform trials: GBM Adaptive Global Innovative Learning Environment (GBM AGILE) and the INdividualized Screening trial of Innovative GBM Therapy (INSIGhT). The future clinical trials landscape in GBM will increasingly involve phase 0, window of opportunity, and adaptive phase I-III studies. Continued collaboration between physicians and biostatisticians will be critical for implementing these trial designs.", "journal": "Current oncology reports", "publication_date": "2023-07-04", "doi": "10.1007/s11912-023-01433-1", "authors": [ "Nicholas S Cho", "Weng Kee Wong", "Phioanh L Nghiemphu", "Timothy F Cloughesy", "Benjamin M Ellingson" ], "keywords": [ "Research Design", "Clinical trials", "Window of opportunity trials", "Adaptive trials", "Phase 0 trials", "Glioblastoma", "Humans", "Adaptive Clinical Trials as Topic", "Drug Development" ] }, { "pmid": "35885067", "title": "Small Molecules and Immunotherapy Agents for Enhancing Radiotherapy in Glioblastoma.", "abstract": "Glioblastoma (GBM) is an aggressive primary brain tumor that is associated with a poor prognosis and quality of life. The standard of care has changed minimally over the past two decades and currently consists of surgery followed by radiotherapy (RT), concomitant and adjuvant temozolomide, and tumor treating fields (TTF). Factors such as tumor hypoxia and the presence of glioma stem cells contribute to the radioresistant nature of GBM. In this review, we discuss the current treatment modalities, mechanisms of radioresistance, and studies that have evaluated promising radiosensitizers. Specifically, we highlight small molecules and immunotherapy agents that have been studied in conjunction with RT in clinical trials. Recent preclinical studies involving GBM radiosensitizers are also discussed.", "journal": "Biomedicines", "publication_date": "2022-07-21", "doi": "10.3390/biomedicines10071763", "authors": [ "Jennifer K Matsui", "Haley K Perlow", "Alex R Ritter", "Rituraj Upadhyay", "Raju R Raval" ], "keywords": [ "tumor hypoxia", "radioresistance", "radiosensitizer", "glioblastoma", "glioma stem cell" ] }, { "pmid": "34884607", "title": "Genetically Modified Cellular Therapies for Malignant Gliomas.", "abstract": "Despite extensive preclinical research on immunotherapeutic approaches, malignant glioma remains a devastating disease of the central nervous system for which standard of care treatment is still confined to resection and radiochemotherapy. For peripheral solid tumors, immune checkpoint inhibition has shown substantial clinical benefit, while promising preclinical results have yet failed to translate into clinical efficacy for brain tumor patients. With the advent of high-throughput sequencing technologies, tumor antigens and corresponding T cell receptors (TCR) and antibodies have been identified, leading to the development of chimeric antigen receptors (CAR), which are comprised of an extracellular antibody part and an intracellular T cell receptor signaling part, to genetically engineer T cells for antigen recognition. Due to efficacy in other tumor entities, a plethora of CARs has been designed and tested for glioma, with promising signs of biological activity. In this review, we describe glioma antigens that have been targeted using CAR T cells preclinically and clinically, review their drawbacks and benefits, and illustrate how the emerging field of transgenic TCR therapy can be used as a potent alternative for cell therapy of glioma overcoming antigenic limitations.", "journal": "International journal of molecular sciences", "publication_date": "2021-11-26", "doi": "10.3390/ijms222312810", "authors": [ "Michael Kilian", "Theresa Bunse", "Wolfgang Wick", "Michael Platten", "Lukas Bunse" ], "keywords": [ "glioma", "Animals", "TCR", "CAR", "Receptors, Chimeric Antigen", "glioblastoma", "adoptive T cell transfer", "brain tumor", "Humans", "Receptors, Antigen, T-Cell", "Glioma", "Brain Neoplasms", "Immunotherapy, Adoptive" ] }, { "pmid": "39409094", "title": "Glioblastoma and Immune Checkpoint Inhibitors: A Glance at Available Treatment Options and Future Directions.", "abstract": "Glioblastoma is known to be one of the most aggressive and fatal human cancers, with a poor prognosis and resistance to standard treatments. In the last few years, many solid tumor treatments have been revolutionized with the help of immunotherapy. However, this type of treatment has failed to improve the results in glioblastoma patients. Effective immunotherapeutic strategies may be developed after understanding how glioblastoma achieves tumor-mediated immune suppression in both local and systemic landscapes. Biomarkers may help identify patients most likely to benefit from this type of treatment. In this review, we discuss the use of immunotherapy in glioblastoma, with an emphasis on immune checkpoint inhibitors and the factors that influence clinical response. A Pubmed data search was performed for all existing information regarding immune checkpoint inhibitors used for the treatment of glioblastoma. All data evaluating the ongoing clinical trials involving the use of ICIs either as monotherapy or in combination with other drugs was compiled and analyzed.", "journal": "International journal of molecular sciences", "publication_date": "2024-10-07", "doi": "10.3390/ijms251910765", "authors": [ "Silvia Mara Baez Rodriguez", "Ligia Gabriela Tataranu", "Amira Kamel", "Serban Turliuc", "Radu Eugen Rizea" ], "keywords": [ "tumor microenvironment", "Immunotherapy", "immune checkpoint inhibitors", "Biomarkers, Tumor", "glioblastoma", "Immune Checkpoint Inhibitors", "Glioblastoma", "Humans", "blood-brain barrier", "immunosuppression", "Brain Neoplasms" ] }, { "pmid": "35456993", "title": "GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma.", "abstract": "Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients with a constitutively active form of EGFR, EGFRvIII, which is associated with shorter survival time. This study examined the effect of GZ17-6.02, a novel anti-cancer agent undergoing phase 1 studies, on two EGFRvIII+ glioblastoma stem cells: D10-0171 and D317. In vitro analyses showed that GZ17-6.02 inhibited the growth of both D10-0171 and D317 cells with IC50 values of 24.84 and 28.28 µg/mL respectively. RNA sequencing and reverse phase protein array analyses revealed that GZ17-6.02 downregulates pathways primarily related to steroid synthesis and cell cycle progression. Interestingly, G17-6.02's mechanism of action involves the downregulation of the recently identified glioblastoma super-enhancer genes WSCD1, EVOL2, and KLHDC8A. Finally, a subcutaneous xenograft model showed that GZ17-6.02 inhibits glioblastoma growth in vivo. We conclude that GZ17-6.02 is a promising combination drug effective at inhibiting the growth of a subset of glioblastomas and our data warrants further preclinical studies utilizing xenograft models to identify patients that may respond to this drug.", "journal": "International journal of molecular sciences", "publication_date": "2022-04-10", "doi": "10.3390/ijms23084174", "authors": [ "Justin Choi", "Zachary A Bordeaux", "Jaimie McKeel", "Cory Nanni", "Nishadh Sutaria" ], "keywords": [ "super-enhancer", "EGFR", "glioblastoma", "ErbB Receptors", "EGFRvIII", "Glioblastoma", "glioblastoma stem cells", "Humans", "Cell Line, Tumor", "Brain Neoplasms", "Antineoplastic Agents" ] }, { "pmid": "39091260", "title": "Stemness, invasion, and immunosuppression modulation in recurrent glioblastoma using nanotherapy.", "abstract": "The recurrent nature of glioblastoma negatively impacts conventional treatment strategies leading to a growing need for nanomedicine. Nanotherapeutics, an approach designed to deliver drugs to specific sites, is experiencing rapid growth and gaining immense popularity. Having potential in reaching the hard-to-reach disease sites, this field has the potential to show high efficacy in combatting glioblastoma progression. The presence of glioblastoma stem cells (GSCs) is a major factor behind the poor prognosis of glioblastoma multiforme (GBM). Stemness potential, heterogeneity, and self-renewal capacity, are some of the properties that make GSCs invade across the distant regions of the brain. Despite advances in medical technology and MRI-guided maximal surgical resection, not all GSCs residing in the brain can be removed, leading to recurrent disease. The aggressiveness of GBM is often correlated with immune suppression, where the T-cells are unable to infiltrate the cancer initiating GSCs. Standard of care therapies, including surgery and chemotherapy in combination with radiation therapy, have failed to tackle all the challenges of the GSCs, making it increasingly important for researchers to develop strategies to tackle their growth and proliferation and reduce the recurrence of GBM. Here, we will focus on the advancements in the field of nanomedicine that has the potential to show positive impact in managing glioblastoma tumor microenvironment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.", "journal": "Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology", "publication_date": "2024", "doi": "10.1002/wnan.1976", "authors": [ "Shrita Sarkar", "Jessica Greer", "Nathaniel J Marlowe", "Angeline Medvid", "Michael E Ivan" ], "keywords": [ "immune suppression", "Animals", "chemotherapy", "Mice", "Neoplasm Invasiveness", "Neoplastic Stem Cells", "drug‐delivery", "glioblastoma", "proliferation", "recurrence", "Immunosuppression Therapy", "nanomedicine", "Glioblastoma", "Humans", "Neoplasm Recurrence, Local", "Nanomedicine", "Brain Neoplasms", "resistance" ] }, { "pmid": "38730705", "title": "Antiretroviral Drug Repositioning for Glioblastoma.", "abstract": "Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.", "journal": "Cancers", "publication_date": "2024-04-30", "doi": "10.3390/cancers16091754", "authors": [ "Sarah R Rivas", "Mynor J Mendez Valdez", "Jay S Chandar", "Jelisah F Desgraves", "Victor M Lu" ], "keywords": [ "drug repurposing", "abacavir", "reverse transcriptase inhibitors", "glioblastoma", "lamivudine", "antiretroviral" ] }, { "pmid": "35406398", "title": "Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers.", "abstract": "Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12-15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood-brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.", "journal": "Cancers", "publication_date": "2022-03-23", "doi": "10.3390/cancers14071627", "authors": [ "Mirna Lechpammer", "Rohan Rao", "Sanjit Shah", "Mona Mirheydari", "Debanjan Bhattacharya" ], "keywords": [ "immune checkpoint inhibitors", "brain tumors", "ultrasound", "immunotherapy", "gliomas" ] }, { "pmid": "34850193", "title": "Optimizing an effective combination of the new microtubule-targeting agent lisavanbulin with standard-of-care therapy for glioblastoma in patient-derived xenograft preclinical models.", "abstract": "No abstract available", "journal": "Neuro-oncology", "publication_date": "2022-03", "doi": "10.1093/neuonc/noab278", "authors": [ "Alain Charest" ], "keywords": [ "Humans", "Antineoplastic Agents, Alkylating", "Microtubules", "Glioblastoma", "Heterografts", "Brain Neoplasms" ] }, { "pmid": "39153669", "title": "Advancing glioblastoma treatment through iron metabolism: A focus on TfR1 and Ferroptosis innovations.", "abstract": "Glioblastoma (GBM) represents a formidable challenge in oncology, characterized by aggressive proliferation and poor prognosis. Iron metabolism plays a critical player in GBM progression, with dysregulated iron uptake and utilization contributing to tumor growth and therapeutic resistance. Iron's pivotal role in DNA synthesis, oxidative stress, and angiogenesis underscores its significance in GBM pathogenesis. Elevated expression of iron transporters, such as transferrin receptor 1 (TfR1), highlights the tumor's reliance on iron for survival. Innovative treatment strategies targeting iron dysregulation hold promise for overcoming therapeutic challenges in GBM management. Approaches such as iron chelation therapies, induction of ferroptosis to nanoparticle-based drug delivery systems exploit iron-dependent vulnerabilities, offering avenues for enhance treatment efficacy and improve patient outcomes. As research advances, understanding the complexities of iron-mediated carcinogenesis provides a foundation for developing precision medicine approaches tailored to combat GBM effectively. This review explores the intricate relationship between iron metabolism and GBM, elucidating its multifaceted implications and therapeutic opportunities. By consolidating the latest insights into iron metabolism in GBM, this review underscores its potential as a therapeutic target for improving patient care in combination with the standard of care approach.", "journal": "International journal of biological macromolecules", "publication_date": "2024-08-15", "doi": "10.1016/j.ijbiomac.2024.134777", "authors": [ "Matías D Caverzan", "Luis E Ibarra" ], "keywords": [ "Iron Chelating Agents", "Receptors, Transferrin", "Animals", "Antigens, CD", "Transferrin receptor", "Iron", "Ferroptosis", "Target therapy", "Glioblastoma", "Humans", "Nanoparticles", "Brain Neoplasms" ] }, { "pmid": "36733367", "title": "Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia.", "abstract": "Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.", "journal": "Frontiers in oncology", "publication_date": "2023-01-17", "doi": "10.3389/fonc.2022.1075559", "authors": [ "Timothy Johanssen", "Laura McVeigh", "Sara Erridge", "Geoffrey Higgins", "Joelle Straehla" ], "keywords": [ "hypoxia", "drug target combination", "radiotherapy", "glioblastoma stem cell", "glioblastoma", "temozolamide", "high throughput screening (HTS)" ] }, { "pmid": "40303349", "title": "Current landscape and future directions of targeted-alpha-therapy for glioblastoma treatment.", "abstract": "Glioblastoma (GB) is the most aggressive malignancy of the central nervous system. Despite two decades of intensive research since the establishment of the standard of care, emerging strategies have yet to produce consistent satisfactory outcomes. Because of its specific localisation and intricate characteristics, GB is a uniquely regulated solid tumour with a strong resistance to therapy. Advances in targeted radionuclide therapy (TRT), particularly with the introduction of a-emitting radionuclides, have unveiled potential avenues for the management of GB. Recent preclinical and clinical studies underscored promising advancements for targeted-α-therapy (TAT), but these therapeutic approaches exhibit a vast design heterogeneity, encompassing diverse radionuclides, vectors, target molecules, and administration modalities. This review seeks to critically assess the therapeutic landscape of GB through the perspective of TAT. Here, the focus is made on the advancements and limitations of in vivo explorations, pilot studies, and clinical trials, to determine the best directions for future investigations. In doing so, we hope to identify existing challenges and draw insights that might pave the way towards a more effective therapeutic approach.", "journal": "Theranostics", "publication_date": "2025-03-31", "doi": "10.7150/thno.106081", "authors": [ "Loris Roncali", "François Hindré", "Edouard Samarut", "Franck Lacoeuille", "Audrey Rousseau" ], "keywords": [ "Molecular Targeted Therapy", "astatine-211", "Animals", "bismuth-213", "Alpha Particles", "Radioisotopes", "Clinical Trials as Topic", "actinium-225", "glioblastoma", "targeted-alpha-therapy", "Glioblastoma", "Humans", "Brain Neoplasms" ] }, { "pmid": "38069593", "title": "Immunotherapy: Advancing glioblastoma treatment-A narrative review of scientific studies.", "abstract": "BACKGROUND: Glioblastoma (GB) is an aggressive and deadly brain tumor with a poor prognosis despite the current standard of care, including surgery, radiation, and chemotherapy. RECENT FINDINGS: In recent years, there has been increasing interest in the potential of immunotherapies, seen to be effective in treating other cancers, in the treatment of GB. This comprehensive review presents an in-depth analysis of the remarkable progress of immunotherapy in GB treatment, focusing on human clinical studies. It also analyzes the current findings, challenges, and limitations that underscore the transformative potential of immunotherapy in managing GB. Of particular significance, it delves into the intriguing interaction of the human microbiome with immunotherapy as a novel avenue for enhancing treatment outcomes of GB. CONCLUSION: This study sheds light on the complex GB therapy landscape and the cutting-edge strategies that show promise for enhancing patient prognosis.", "journal": "Cancer reports (Hoboken, N.J.)", "publication_date": "2023-12-09", "doi": "10.1002/cnr2.1947", "authors": [ "Sagun Tiwari", "Zhenxiang Han" ], "keywords": [ "glioma", "tumor", "glioblastoma", "immune checkpoint", "microbiome", "microbe", "immunotherapy", "cancer", "clinical studies" ] }, { "pmid": "34503065", "title": "Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy.", "abstract": "Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.", "journal": "Cancers", "publication_date": "2021-08-24", "doi": "10.3390/cancers13174255", "authors": [ "Rikke Sick Andersen", "Atul Anand", "Dylan Scott Lykke Harwood", "Bjarne Winther Kristensen" ], "keywords": [ "glioblastoma", "TAM", "tumor-associated microglia and macrophages", "crosstalk", "therapeutic strategies", "microenvironment" ] }, { "pmid": "38437669", "title": "Evolving concepts in margin strategies and adaptive radiotherapy for glioblastoma: A new future is on the horizon.", "abstract": "Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed.", "journal": "Neuro-oncology", "publication_date": "2024-03", "doi": "10.1093/neuonc/noad258", "authors": [ "Chia-Lin Tseng", "K Liang Zeng", "Eric A Mellon", "Scott G Soltys", "Mark Ruschin" ], "keywords": [ "radiotherapy margins", "glioblastoma", "Neurology", "Radiation Oncology", "MR-Linac", "Chemoradiotherapy", "Glioblastoma", "adaptive radiotherapy", "Humans" ] }, { "pmid": "33689795", "title": "Adding high-dose celecoxib to increase effectiveness of standard glioblastoma chemoirradiation.", "abstract": "Over one hundred clinical trials since 2005 have failed to significantly improve the prognosis of glioblastoma. Since 2005, the standard of care has been maximal resection followed by 60Gy irradiation over six weeks with daily temozolomide. With this, a median survival of 2 years can be expected. This short paper reviewed how the pharmacodynamic attributes of an EMA/FDA approved, cheap, generic drug to treat pain, celecoxib, intersect with pathophysiological elements driving glioblastoma growth, such that growth drive inhibition can be expected from celecoxib. The two main attributes of celecoxib are carbonic anhydrase inhibition and cyclooxygenase-2 inhibition. Both attributes individually have been in active study as adjuncts during current cancer treatment, including that of glioblastoma. That research is briefly reviewed here. This paper concludes from the collected data, that starting celecoxib, 600 to 800mg twice daily before surgery and continuing it through the chemoirradiation phase of treatment would be a low-risk intervention with sound rationale.", "journal": "Annales pharmaceutiques francaises", "publication_date": "2021-03-06", "doi": "10.1016/j.pharma.2021.03.001", "authors": [ "R E Kast" ], "keywords": [ "Glioblastome", "Anhydrase carbonique", "CUSP9", "Cyclooxygenase", "Carbonic anhydrase", "Cyclooxygénase", "Célécoxib", "Hypoxia", "Glioblastoma", "Humans", "Celecoxib", "Hypoxie", "Cyclooxygenase 2", "Temozolomide" ] }, { "pmid": "38105543", "title": "Metabolism and signaling crosstalk in glioblastoma progression and therapy resistance.", "abstract": "Glioblastoma is the most common form of primary malignant brain tumor in adults and one of the most lethal human cancers, with high recurrence and therapy resistance. Glioblastoma cells display extensive genetic and cellular heterogeneity, which precludes a unique and common therapeutic approach. The standard of care in glioblastoma patients includes surgery followed by radiotherapy plus concomitant temozolomide. As in many other cancers, cell signaling is deeply affected due to mutations or alterations in the so-called molecular drivers. Moreover, glioblastoma cells undergo metabolic adaptations to meet the new demands in terms of energy and building blocks, with an increasing amount of evidence connecting metabolic transformation and cell signaling deregulation in this type of aggressive brain tumor. In this review, we summarize some of the most common alterations both in cell signaling and metabolism in glioblastoma, presenting an integrative discussion about how they contribute to therapy resistance. Furthermore, this review aims at providing a comprehensive overview of the state-of-the-art of therapeutic approaches and clinical trials exploiting signaling and metabolism in glioblastoma.", "journal": "Molecular oncology", "publication_date": "2023-12-26", "doi": "10.1002/1878-0261.13571", "authors": [ "Laura Zarzuela", "Raúl V Durán", "Mercedes Tomé" ], "keywords": [ "therapy resistance", "Animals", "metabolism", "glioblastoma", "temozolomide", "Disease Progression", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "cell signaling", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "37547266", "title": "Feasibility and tolerability of trofosfamide and etoposide in progressive glioblastoma.", "abstract": "BACKGROUND: Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. METHODS: We collected clinicopathological data from adult progressive glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators' discretion balanced for tumor entity and canonical prognostic factors served as control. RESULTS: A total of n = 22 progressive glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 vs 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, P = .0274) and median overall survival (9.0 vs 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, P = .0003) were significantly prolonged compared to the control cohort (n = 17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n = 16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n = 15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n = 11/15, 73%). CONCLUSIONS: This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients. The observed survival outcomes might suggest potential beneficial effects. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective trial.", "journal": "Neuro-oncology advances", "publication_date": "2023-07-20", "doi": "10.1093/noajnl/vdad090", "authors": [ "Teresa Schmidt", "Sarina Agkatsev", "Jonas Feldheim", "Christoph Oster", "Tobias Blau" ], "keywords": [ "progressive glioblastoma", "trofosfamide", "etoposide", "glioblastoma" ] }, { "pmid": "39239018", "title": "Surgical outcomes of glioblastoma multiforme in low and middle-income countries: current state and future directions.", "abstract": "Glioblastoma (GBM) is a highly aggressive and deadly brain tumor. The challenges in managing GBM in low- and middle-income countries (LMICs) have been underexplored. This review provides a review of surgical management techniques, challenges, outcomes, and future directions for GBM treatment in LMICs. A search of academic databases yielded studies from various LMICs, focusing on surgical management techniques and their outcomes. The data were analyzed in the context of socio-economic, cultural, and infrastructural factors. Comparative analyses were performed to highlight disparities between LMICs and high-income countries. GBM management in LMICs faces multi-faceted challenges, including healthcare infrastructure deficiencies, delayed diagnosis, high treatment costs, cultural beliefs, and limited research funding. This adversely affects patient outcomes and survival rates. Surgical excision followed by radiation and chemotherapy remains the standard of care, but LMICs have not significantly benefited from recent advancements in GBM management. Intraoperative neurosurgery ultrasound is identified as an affordable and practical alternative for LMICs. Patient outcomes following GBM surgery in LMICs vary widely, making early detection challenging. Cultural sensitivity and ethical considerations are crucial factors in improving healthcare practices. Surgical management of GBM in LMICs is hindered by complex challenges that require multi-faceted interventions. By addressing socio-economic, cultural, and infrastructural factors, LMICs can improve GBM care and outcomes. Raising awareness and advocating for change are crucial steps in this process.", "journal": "Annals of medicine and surgery (2012)", "publication_date": "2024-07-08", "doi": "10.1097/MS9.0000000000002362", "authors": [ "Muili Abdulbasit Opeyemi", "Nicholas Aderinto", "Ayodeji Akinmeji", "Fatihi Bamigbola Mustapha", "Jolayemi Mustapha Mubarak" ], "keywords": [ "surgery", "challenges", "glioblastoma" ] }, { "pmid": "39167243", "title": "Dendritic cell vaccine for glioblastoma: an updated meta-analysis and trial sequential analysis.", "abstract": "BACKGROUND: Dendritic cell (DC) vaccine is an emerging immunotherapy that could potentially improve glioblastoma survival. The first phase III clinical trial of DC vaccine was recently published. This meta-analysis aims to update and reappraise existing evidence on the efficacy of DC vaccine in patients with glioblastoma. METHODS: We searched PubMed, Embase, and Cochrane Library for clinical trials of DC vaccine for glioblastoma. The quality of the studies was assessed using the RoB 2.0 and ROBINS-I tools. The results of overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Summary effects were evaluated using random effects models. Trial sequential analysis (TSA) was performed. RESULTS: Seven clinical trials involving 3,619 patients were included. DC vaccine plus standard care was associated with significantly improved OS (HR = 0.71; 95% CI, 0.57 - 0.88) and PFS (HR = 0.65; 95% CI, 0.43 - 0.98). In the subgroup of newly diagnosed glioblastoma, DC vaccine was associated with improved PFS (HR = 0.59; 95% CI, 0.39 - 0.90). TSA of OS showed that the cumulative z-score line for the DC vaccine crossed the benefit boundary and reached the required sample size. TSA of PFS and subgroup analysis of newly diagnosed glioblastoma showed that the required sample size was not reached. CONCLUSIONS: This updated meta-analysis, which included the first phase III trial of a DC vaccine for glioblastoma, demonstrated that the DC vaccine was associated with improved OS. Moreover, TSA showed that the required sample size was reached, indicating a true-positive result. Future studies are required for patient subgroups with newly diagnosed and recurrent glioblastoma.", "journal": "Journal of neuro-oncology", "publication_date": "2024-08-21", "doi": "10.1007/s11060-024-04798-w", "authors": [ "Chia-En Wong", "Yu Chang", "Pei-Wen Chen", "Yan-Ta Huang", "Yu-Cheng Chang" ], "keywords": [ "Immunotherapy", "Trial sequential analysis", "Dendritic cell vaccine", "Clinical Trials as Topic", "Cancer Vaccines", "Meta-analysis", "Glioblastoma", "Humans", "Dendritic Cells", "Brain Neoplasms" ] }, { "pmid": "41379280", "title": "Efficacy of ketogenic metabolic therapy as an adjuvant to the current standard of care in the treatment of glioblastoma: A systematic review of clinical trials.", "abstract": "Glioblastoma is a diffuse, heterogenous tumour with a poor prognosis as current therapeutic options have limited efficacy. As a result, research aims to explore new treatment options which exploit the hallmarks of cancer. This review aimed to understand the breadth of research considering ketogenic metabolic therapy (KMT) as an adjuvant to standard therapy. KMT aims to improve overall survival by exploiting the metabolic reprogramming exclusive to neoplastic cells. Preclinical trials show benefits in KMT when used alongside radiotherapy, through increasing anti-tumour effects compared to controls. Literature searches conducted over three databases, in line with PRISMA guidelines, collated studies relevant to KMT and glioblastoma. Six prospective studies and one retrospective study met the inclusion criteria for this review. Data regarding participants, interventions and survival were extracted. Studies included used small numbers of participants, as many aimed to assess the feasibility of larger-scale trials, which increases errors and bias of results. Furthermore, direct comparison between trials was limited due to study heterogeneity, as each trial used differing parameters and diet compositions. As a result, no definitive conclusions could be made. Future studies should use larger cohorts with standardised parameters so results are representative, and comparisons can be made to evaluate efficacy.", "journal": "Medical oncology (Northwood, London, England)", "publication_date": "2025-12-11", "doi": "10.1007/s12032-025-03165-7", "authors": [ "Emily McKerill", "Joecelyn Kirani Tan", "Chethana Krishna Rao", "Christian A Linares", "Soirindhri Banerjee" ], "keywords": [ "Diet, Ketogenic", "Adjuvant", "Efficacy", "Clinical Trials as Topic", "Ketogenic metabolic therapy", "Standard of Care", "Brain tumour", "Glioblastoma", "Humans", "Brain Neoplasms" ] }, { "pmid": "37796104", "title": "Investigational treatment strategies in glioblastoma: progress made and barriers to success.", "abstract": "INTRODUCTION: Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005 comprises maximal safe resection followed by radiation with concurrent and adjuvant temozolomide; more recently, the addition of tumor treating fields was approved in the newly diagnosed and recurrent disease settings. AREAS COVERED: Searches of PubMed, Cochrane Library, and ClinicalTrials.gov provided a foundation for this review. We first describe early research including carmustine wafers, brachytherapy, anti-angiogenesis, and immune checkpoint inhibition for glioblastoma. Next, we discuss challenges precluding the translation of preclinical successes. This is followed by a description of promising treatments such as chimeric antigen receptor T-cell therapy as well as the recent qualified successes of cancer vaccinations. Non-immunotherapy trials are also highlighted, and ongoing or pending phase 2 and 3 clinical trials are codified in study tables. EXPERT OPINION: Unfortunately, hundreds of trials, including of agents effective in systemic malignancy, have not drastically changed management of glioblastoma. This may reflect unique resistance mechanisms and highlights a need for multimodality treatments beyond surgery, radiation, and conventional chemotherapy. Novel techniques, such as those in the emerging field of cancer neuroscience, may help uncover tolerable and effective regimens for this lethal malignancy.", "journal": "Expert opinion on investigational drugs", "publication_date": "2023-11-06", "doi": "10.1080/13543784.2023.2267982", "authors": [ "Thomas A Nelson", "Jorg Dietrich" ], "keywords": [ "Combined Modality Therapy", "glioblastoma", "cancer vaccination", "immunotherapy", "chimeric antigen receptor T-cell therapy", "Cancer neuroscience", "Glioblastoma", "Humans", "Therapies, Investigational", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "39272879", "title": "Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials.", "abstract": "Glioblastoma (GBM) is the most prevalent central nervous system tumour (CNS). Patients with GBM have a dismal prognosis of 15 months, despite an intensive treatment schedule consisting of surgery, chemoradiation and concurrent chemotherapy. In the last decades, many trials have been performed investigating small molecule inhibitors, which target specific genes involved in tumorigenesis. So far, these trials have been unsuccessful, and standard of care for GBM patients has remained the same since 2005. This review gives an overview of trials investigating small molecule inhibitors on their own, combined with chemotherapy or other small molecule inhibitors. We discuss possible resistance mechanisms in GBM, focussing on intra- and intertumoral heterogeneity, bypass mechanisms and the influence of the tumour microenvironment. Moreover, we emphasise how combining inhibitors can help overcome these resistance mechanisms. We also address strategies for improving trial outcomes through modifications to their design. In summary, this review aims to elucidate different resistance mechanisms against small molecule inhibitors, highlighting their significance in the search for novel therapeutic combinations to improve the overall survival of GBM patients.", "journal": "Cancers", "publication_date": "2024-08-29", "doi": "10.3390/cancers16173021", "authors": [ "Linde Hoosemans", "Marc Vooijs", "Ann Hoeben" ], "keywords": [ "small molecule inhibitors", "glioblastoma", "clinical trials", "tyrosine kinase inhibitors", "resistance" ] }, { "pmid": "34783762", "title": "Nanomedicine in the treatment of Glioblastoma.", "abstract": "The current standard of care in glioblastoma management is surgery followed by chemotherapy and radiotherapy. Temozolomide is an alkylating agent most commonly used with a few other second line options. The efficacy of systemic chemotherapy in brain malignancies is limited due to the nature of the blood-brain barrier. Nanomedicine offers one avenue of improving drug delivery to these tumours in a more focussed and effective way in higher doses than currently possible, while simultaneously reducing systemic toxicity.", "journal": "JPMA. The Journal of the Pakistan Medical Association", "publication_date": "2021-11", "doi": null, "authors": [ "Syeda Kubra Kishwar Jafri", "Syed Sarmad Bukhari", "Muhammad Shahzad Shamim" ], "keywords": [ "Blood-Brain Barrier", "Antineoplastic Agents, Alkylating", "Glioblastoma multiforme, brain tumour, nanotechnology", "Glioblastoma", "Humans", "Nanomedicine", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "36259473", "title": "Angiogenesis and Its Targeting in Glioblastoma with Focus on Clinical Approaches.", "abstract": "Angiogenesis is a characteristic of glioblastoma (GBM), the most fatal and therapeutic-resistant brain tumor. Highly expressed angiogenic cytokines and proliferated microvascular system made anti-angiogenesis treatments a thoroughly plausible approach for GBM treatment. Many trials have proved to be not only as a safe but also as an effective approach in GBM retardation in a certain time window as seen in radiographic response rates; however, they have failed to implement significant improvements in clinical manifestation whether alone or in combination with radio/chemotherapy. Bevasizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, is the only agent that exerts meaningful clinical influence by improving progression-free survival (PFS) and partially alleviate clinical symptoms, nevertheless, it could not prolong the overall survival (OS) in patients with GBM. The data generated from phase II trials clearly revealed a correlation between elevated reperfusion, subsequent to vascular normalization induction, and improved clinical outcomes which explicitly indicates anti-angiogenesis treatments are beneficial. In order to prolong these initial benefits observed in a certain period of time after anti-angiogenesis targeting, some aspects of the therapy should be tackled: recognition of other bypass angiogenesis pathways activated following antiangiogenesis therapy, identification of probable pathways that induce insensitivity to shortage of blood supply, and classifying the patients by mapping their GBM-related gene profile as biomarkers to predict their responsiveness to therapy. Herein, the molecular basis of brain vasculature development in normal and tumoral conditions is briefly discussed and it is explained how \"vascular normalization\" concept opened a window to a better comprehension of some adverse effects observed in anti-angiogenesis therapy in clinical condition. Then, the most targeted angiogenesis pathways focused on ligand/receptor interactions in GBM clinical trials are reviewed. Lastly, different targeting strategies applied in anti-angiogenesis treatment are discussed.", "journal": "Cell journal", "publication_date": "2022-10-01", "doi": "10.22074/cellj.2022.8154", "authors": [ "Fatemeh Daneshimehr", "Zahra Barabadi", "Shahrokh Abdolahi", "Masoud Soleimani", "Javad Verdi" ], "keywords": [ "Tyrosine-Kinase Receptors", "Clinical trial", "Cell Adhesion Molecules", "Angiogenesis pathway", "Glioblastoma" ] }, { "pmid": "34046356", "title": "A Comparison Between Chemo-Radiotherapy Combined With Immunotherapy and Chemo-Radiotherapy Alone for the Treatment of Newly Diagnosed Glioblastoma: A Systematic Review and Meta-Analysis.", "abstract": "BACKGROUND: Immunotherapy for GBM is an emerging field which is increasingly being investigated in combination with standard of care treatment options with variable reported success rates. OBJECTIVE: To perform a systematic review of the available data to evaluate the safety and efficacy of combining immunotherapy with standard of care chemo-radiotherapy following surgical resection for the treatment of newly diagnosed GBM. METHODS: A literature search was performed for published clinical trials evaluating immunotherapy for GBM from January 1, 2000, to October 1, 2020, in PubMed and Cochrane using PICOS/PRISMA/MOOSE guidelines. Only clinical trials with two arms (combined therapy vs. control therapy) were included. Outcomes were then pooled using weighted random effects model for meta-analysis and compared using the Wald-type test. Primary outcomes included 1-year overall survival (OS) and progression-free survival (PFS), secondary outcomes included severe adverse events (SAE) grade 3 or higher. RESULTS: Nine randomized phase II and/or III clinical trials were included in the analysis, totaling 1,239 patients. The meta-analysis revealed no statistically significant differences in group's 1-year OS [80.6% (95% CI: 68.6%-90.2%) vs. 72.6% (95% CI: 65.7%-78.9%), p = 0.15] or in 1-year PFS [37% (95% CI: 26.4%-48.2%) vs. 30.4% (95% CI: 25.4%-35.6%) p = 0.17] when the immunotherapy in combination with the standard of care group (combined therapy) was compared to the standard of care group alone (control). Severe adverse events grade 3 to 5 were more common in the immunotherapy and standard of care group than in the standard of care group (47.3%, 95% CI: 20.8-74.6%, vs 43.8%, 95% CI: 8.7-83.1, p = 0.81), but this effect also failed to reach statistical significance. CONCLUSION: Our results suggests that immunotherapy can be safely combined with standard of care chemo-radiotherapy without significant increase in grade 3 to 5 SAE; however, there is no statistically significant increase in overall survival or progression free survival with the combination therapy.", "journal": "Frontiers in oncology", "publication_date": "2021-05-11", "doi": "10.3389/fonc.2021.662302", "authors": [ "Montserrat Lara-Velazquez", "Jack M Shireman", "Eric J Lehrer", "Kelsey M Bowman", "Henry Ruiz-Garcia" ], "keywords": [ "glioma", "high-grade glioma", "vaccine", "chemo-radiotherapy", "newly diagnosed glioblastoma", "immunotherapy" ] }, { "pmid": "39346924", "title": "Immune checkpoint pathways in glioblastoma: a diverse and evolving landscape.", "abstract": "Immune checkpoint (IC) inhibition in glioblastoma (GBM) has not shown promising results in the last decade compared to other solid tumors. Several factors contributing to the lack of immunotherapy response include the profound immunosuppressive nature of GBM, highly redundant signaling pathways underlying immune checkpoints, and the negative immunogenic impact of current standard of care on the tumor microenvironment. In this review, we will discuss various ICs in the context of GBM, their interplay with the tumor immune microenvironment, relevant pre-clinical and clinical studies, and the impact of current treatment modalities on GBM IC blockade therapy. Understanding the molecular mechanisms that drive ICs, and how they contribute to an immunosuppressive tumor microenvironment is critical in advancing IC inhibition therapy in GBM. Furthermore, revisiting current treatment modalities and their impact on the immune landscape is instrumental in designing future combinatorial therapies that may overcome treatment resistance.", "journal": "Frontiers in immunology", "publication_date": "2024-09-13", "doi": "10.3389/fimmu.2024.1424396", "authors": [ "Julio F Inocencio", "Stefan Mitrasinovic", "Mohammad Asad", "Ian F Parney", "Xingxing Zang" ], "keywords": [ "Animals", "Immunotherapy", "immune checkpoints", "tumor immunosuppression", "Immune Checkpoint Proteins", "glioblastoma", "immunotherapy", "Immune Checkpoint Inhibitors", "immune microenvironment", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "37995317", "title": "Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?", "abstract": "Glioblastoma (GBM)'s median overall survival is almost 21 months. Six phase 3 immunotherapy clinical trials have recently been published, yet 5/6 did not meet approval by regulatory bodies. For the sixth, approval is uncertain. Trial failures result from multiple factors, ranging from intrinsic tumor biology to clinical trial design. Understanding the clinical and basic science of these 6 trials is compelled by other immunotherapies reaching the point of advanced phase 3 clinical trial testing. We need to understand more of the science in human GBMs in early trials: the \"window of opportunity\" design may not be best to understand complex changes brought about by immunotherapeutic perturbations of the GBM microenvironment. The convergence of increased safety of image-guided biopsies with \"multi-omics\" of small cell numbers now permits longitudinal sampling of tumor and biofluids to dissect the complex temporal changes in the GBM microenvironment as a function of the immunotherapy.", "journal": "Neuro-oncology", "publication_date": "2024-02", "doi": "10.1093/neuonc/noad211", "authors": [ "Ethan Chen", "Alexander L Ling", "David A Reardon", "E Antonio Chiocca" ], "keywords": [ "Clinical Trials, Phase III as Topic", "tumor microenvironment", "Immunotherapy", "multi-omics", "phase 0 clinical trial", "image-guided biopsy", "window of opportunity clinical trial", "Glioblastoma", "Tumor Microenvironment", "Humans", "Brain Neoplasms" ] }, { "pmid": "38932383", "title": "Glioblastoma Vaccines as Promising Immune-Therapeutics: Challenges and Current Status.", "abstract": "Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard treatments including surgical resection, radiotherapy, and chemotherapy, have failed to significantly improve the prognosis of glioblastoma patients. Currently, immunotherapeutic approaches based on vaccines, chimeric antigen-receptor T-cells, checkpoint inhibitors, and oncolytic virotherapy are showing promising results in clinical trials. The combination of different immunotherapeutic approaches is proving satisfactory and promising. In view of the challenges of immunotherapy and the resistance of glioblastomas, the treatment of these tumors requires further efforts. In this review, we explore the obstacles that potentially influence the efficacy of the response to immunotherapy and that should be taken into account in clinical trials. This article provides a comprehensive review of vaccine therapy for glioblastoma. In addition, we identify the main biomarkers, including isocitrate dehydrogenase, epidermal growth factor receptor, and telomerase reverse transcriptase, known as potential immunotherapeutic targets in glioblastoma, as well as the current status of clinical trials. This paper also lists proposed solutions to overcome the obstacles facing immunotherapy in glioblastomas.", "journal": "Vaccines", "publication_date": "2024-06-12", "doi": "10.3390/vaccines12060655", "authors": [ "Asmae Squalli Houssaini", "Salma Lamrabet", "Jean Paul Nshizirungu", "Nadia Senhaji", "Mohammed Sekal" ], "keywords": [ "TERT", "vaccine", "EGFR", "glioblastoma", "IDH", "immunotherapy" ] }, { "pmid": "40346033", "title": "KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.", "abstract": "Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.", "journal": "Nature communications", "publication_date": "2025-05-09", "doi": "10.1038/s41467-025-59503-w", "authors": [ "Anca B Mihalas", "Sonali Arora", "Samantha A O'Connor", "Heather M Feldman", "Christine E Cucinotta" ], "keywords": [ "Neural Stem Cells", "Animals", "Mice", "Neoplastic Stem Cells", "Cell Proliferation", "Gene Expression Regulation, Neoplastic", "Glioblastoma", "Humans", "Histone Acetyltransferases", "Cell Line, Tumor", "Proto-Oncogene Proteins c-myc", "Brain Neoplasms" ] }, { "pmid": "35615860", "title": "Novel therapeutics and drug-delivery approaches in the modulation of glioblastoma stem cell resistance.", "abstract": "Glioblastoma (GBM) is a deadly malignancy with a poor prognosis. An important factor contributing to GBM recurrence is high resistance of GBM cancer stem cells (GSCs). While temozolomide (TMZ), has been shown to consistently extend survival, GSCs grow resistant to TMZ through upregulation of DNA damage repair mechanisms and avoidance of apoptosis. Since a single-drug approach has failed to significantly alter prognosis in the past 15 years, unique approaches such as multidrug combination therapy together with distinctive targeted drug-delivery approaches against cancer stem cells are needed. In this review, a rationale for multidrug therapy using a targeted nanotechnology approach that preferentially target GSCs is proposed with discussion and examples of drugs, nanomedicine delivery systems, and targeting moieties.", "journal": "Therapeutic delivery", "publication_date": "2022-05-26", "doi": "10.4155/tde-2021-0086", "authors": [ "Shelby B Smiley", "Hamideh Zarrinmayeh", "Sudip K Das", "Karen E Pollok", "Michael W Vannier" ], "keywords": [ "GBM", "glioblastoma", "theranostics", "Glioblastoma", "Humans", "nanomedicine", "solid-lipid nanoparticle", "cancer stem cells", "CSC", "CD44", "paclitaxel", "idasanutlin", "Temozolomide", "Neoplastic Stem Cells", "CD133", "Drug Therapy, Combination", "temozolomide", "Cell Line, Tumor", "Leprostatic Agents", "nanoparticle" ] }, { "pmid": "40595067", "title": "A phase 1 safety and feasibility trial of a ketogenic diet plus standard of care for patients with recently diagnosed glioblastoma.", "abstract": "Despite great interest, there is limited clinical evidence to support the use of a ketogenic diet (KD) for cancer patients. We conducted a single-arm phase 1 trial of a KD among patients with recently diagnosed glioblastoma (GBM) receiving standard-of-care (SOC) treatment. Adults with GBM within 3 months of diagnosis followed a supervised 16-week intervention of a 3:1 KD (Fat(g): Carbohydrate + Protein(g)) plus SOC chemoradiation. The primary outcome was safety, evaluated by weekly assessments of weight and body mass index (BMI). Secondary outcomes included feasibility (pre-specified as > 50% of patients maintaining blood ketone levels > 0.3 mM over 50% of study days), progression-free survival (PFS), overall survival (OS), health-related quality-of-life, and cognitive function. Twice daily blood glucose and ketones, weight/BMI, physical activity, and sleep were assessed by remote monitoring. Seventeen patients were evaluable: 53% women, median age 55, median Karnofsky Performance Status 85. All subjects met the primary safety objective with no instances of excessive weight loss or related serious adverse events. Adherence was high: all 17 patients maintained nutritional ketosis (≥ 0.3 mM/dL) > 50% of study days. Median PFS and OS were 12.9 months and 29.4 months from KD initiation respectively. Quality of Life, symptom control, and cognitive function remained stable or improved, although these did not reach statistical significance. This phase 1 trial demonstrates that KD is safe and feasible for GBM patients receiving SOC, may improve outcomes, and provides a foundation for an NCI-funded multicenter randomized diet trial to assess efficacy that is currently underway.", "journal": "Scientific reports", "publication_date": "2025-07-01", "doi": "10.1038/s41598-025-06675-6", "authors": [ "L J Amaral", "Gillian Gresham", "Sungjin Kim", "Mourad Tighiouart", "Thomas A Nelson" ], "keywords": [ "Cancer metabolism", "Treatment Outcome", "Glioblastoma", "Humans", "Male", "Ketosis", "Warburg effect", "Middle Aged", "Ketogenic diets", "Female", "Adult", "Aged", "Physical activity", "Quality of life", "Supportive care", "Feasibility Studies", "Diet, Ketogenic", "Quality of Life", "Standard of Care", "Brain Neoplasms" ] }, { "pmid": "39516641", "title": "Viruses in glioblastoma: an update on evidence and clinical trials.", "abstract": "BACKGROUND: Glioblastoma (GB) is a lethal and aggressive brain tumour. While molecular characteristics of GB is studied extensively, the aetiology of GB remains uncertain. The interest in exploring viruses as a potential contributor to the development of GB stems from the notion that viruses are known to play a key role in pathogenesis of other human cancers such as cervical cancer. Nevertheless, the role of viruses in GB remains controversial. METHODS: This review delves into the current body of knowledge surrounding the presence of viruses in GB as well as provide updates on clinical trials examining the potential inclusion of antiviral therapies as part of the standard of care protocol. CONCLUSIONS: The review summarises current evidences and important gaps in our knowledge related to the presence of viruses in GB.", "journal": "BJC reports", "publication_date": "2024-04-19", "doi": "10.1038/s44276-024-00051-z", "authors": [ "Bavani Gunasegaran", "Caroline L Ashley", "Felix Marsh-Wakefield", "Gilles J Guillemin", "Benjamin Heng" ], "keywords": [] }, { "pmid": "39408897", "title": "Review of Novel Surgical, Radiation, and Systemic Therapies and Clinical Trials in Glioblastoma.", "abstract": "Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite an established standard of care including surgical resection, radiation therapy, and chemotherapy, GBM unfortunately is associated with a dismal prognosis. Therefore, researchers are extensively evaluating avenues to expand GBM therapy and improve outcomes in patients with GBM. In this review, we provide a broad overview of novel GBM therapies that have recently completed or are actively undergoing study in clinical trials. These therapies expand across medical, surgical, and radiation clinical trials. We additionally review methods for improving clinical trial design in GBM.", "journal": "International journal of molecular sciences", "publication_date": "2024-09-30", "doi": "10.3390/ijms251910570", "authors": [ "Allison R Valerius", "Lauren M Webb", "Anna Thomsen", "Eric J Lehrer", "William G Breen" ], "keywords": [ "radiation therapy", "high-grade glioma", "Combined Modality Therapy", "Clinical Trials as Topic", "glioblastoma", "review of therapy", "immunotherapy", "targeted molecular therapy", "Glioblastoma", "Humans", "surgical therapy", "Brain Neoplasms" ] }, { "pmid": "39386927", "title": "Clinical and translational advances in primary brain tumor therapy with a focus on glioblastoma-A comprehensive review of the literature.", "abstract": "This comprehensive review paper examines the most updated state of research on glioblastoma, an aggressive brain tumor with limited treatment options. By analyzing 76 recent studies, from translational and basic sciences, to clinical trials, we highlight various aspects of glioblastoma and shed light on potential therapeutic strategies. The interplay between tumor cells, neural progenitor cells, and the tumor microenvironment is explored. Targeting the PI3K-Akt-mTOR pathway through extracellular-vesicle (EV)-mediated signaling emerges as a potential therapeutic strategy. Personalized modeling approaches utilizing patient-specific MRI data offer promise for optimizing treatment strategies. The response of glioblastoma stem cells (GSCs) to different treatment modalities is examined, emphasizing the need to inhibit the transformation of proneural (PN) GSCs into resistant mesenchymal (MES) GSCs. Metabolic therapy and combination therapies show potential in reversing treatment resistance and inhibiting both PN and MES GSCs. Immunotherapy, targeted approaches, and molecular dynamics in gliomas are discussed, providing insights into early-stage diagnosis and treatment. Additionally, the potential use of Zika virus as an oncolytic agent is explored. Analysis of phase 0 to 3 clinical trials reveal promising outcomes for various experimental treatments, highlighting the importance of combination therapies, predictive signatures, and patient selection strategies. Specific compounds demonstrate potential therapeutic benefits and tolerability. Phase 3 trials indicate the efficacy of DCVax-L in improving survival rates and depatux-m in prolonging progression-free survival. These findings emphasize the importance of personalized treatment approaches and continued exploration of targeted therapies, immunotherapies, and tumor biology understanding in shaping the future of glioblastoma treatment.", "journal": "World neurosurgery: X", "publication_date": "2024-09-21", "doi": "10.1016/j.wnsx.2024.100399", "authors": [ "Muhammad Saqib", "Aanus Zahoor", "Ahmed Rahib", "Amna Shamim", "Hassan Mumtaz" ], "keywords": [ "Cancer stem cells", "Glial cells", "Immunotherapy", "Neural stem cells", "Brain tumors", "Neuron", "Glioma" ] }, { "pmid": "40868217", "title": "Glioblastoma: From Pathophysiology to Novel Therapeutic Approaches.", "abstract": "Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Despite the current standard of care therapy, including maximal surgical resection, chemoradiation, and tumor-treating fields, prognosis remains poor. Therapeutic failure is driven by an immunosuppressive tumor microenvironment, poor drug penetration across the blood-brain barrier, and robust resistance mechanisms. Epigenetic alterations further compound treatment resistance by enhancing DNA repair and promoting survival pathways. Molecular profiling has identified key prognostic and predictive biomarkers. Gene expression analyses have delineated GBM subtypes, each with distinct molecular features and therapeutic vulnerabilities that hinder successful clinical translation. This review integrates the pathophysiological, diagnostic, and therapeutic landscape of GBM to inform of future strategies for improved patient outcomes.", "journal": "Biomedicines", "publication_date": "2025-08-12", "doi": "10.3390/biomedicines13081963", "authors": [ "Anatevka Ribeiro", "Gianna Fote", "Alexander Himstead", "Michelle Zheng", "Emma Elliott" ], "keywords": [ "vaccine", "laser interstitial thermal therapy (LITT)", "glioblastoma", "theranostics", "GammaTile®", "chimeric antigen receptor (CAR) T-cell therapy", "immunotherapy" ] }, { "pmid": "38777680", "title": "Intracranial CAR-T cell delivery in glioblastoma patients.", "abstract": "Chimeric antigen receptor (CAR)-T cell therapy is emerging as a promising approach for improving outcomes in high-grade glioma. Here, we highlight three recent studies that reported safety and feasibility of intracranial CAR-T cell administration in patients with glioblastoma (GBM) as well as preliminary evidence of potential responses, supporting further investigations of this approach.", "journal": "Trends in cancer", "publication_date": "2024-05-22", "doi": "10.1016/j.trecan.2024.05.002", "authors": [ "Philippa Vaughn-Beaucaire", "Moon Jung Choi", "Olin Liang", "Sean E Lawler" ], "keywords": [ "clinical trial", "Receptors, Chimeric Antigen", "glioblastoma", "immunotherapy", "Glioblastoma", "Humans", "CAR-T cells", "T-Lymphocytes", "Brain Neoplasms", "Immunotherapy, Adoptive" ] }, { "pmid": "37196077", "title": "Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production.", "abstract": "During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients' tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production.", "journal": "Science advances", "publication_date": "2023-05-17", "doi": "10.1126/sciadv.ade7236", "authors": [ "Ella N Perrault", "Jack M Shireman", "Eunus S Ali", "Peiyu Lin", "Isabelle Preddy" ], "keywords": [ "Ribonucleotide Reductases", "Glioblastoma", "Drug Resistance, Neoplasm", "Humans", "Cell Line, Tumor", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "36100970", "title": "Current therapeutic options for glioblastoma and future perspectives.", "abstract": "INTRODUCTION: Glioblastoma is a malignant primary brain tumor that affects approximately 250,000 new patients per year worldwide. It is among the most difficult cancers to treat, and 5-year survival rates remain low. Standard therapies for glioblastoma include surgical resection, radiation therapy and systemic chemotherapy. AREAS COVERED: We conducted a search of the literature on therapeutic options for glioblastoma on Pubmed. We also searched abstracts from the American Society of Clinical Oncology, Society for Neuro-Oncology, European Association of Neuro-Oncology and American Association for Cancer Research. We also searched the U.S. National Library of Medicine clinical trials database. We discuss therapeutic options for newly diagnosed glioblastoma, mainly temozolomide, lomustine and tumor treating fields (TTF). Lastly, we discuss therapeutics for recurrent glioblastomas and agents under investigation in clinical trials. EXPERT OPINION: Enrollment in clinical trials is encouraged for both newly diagnosed and recurrent glioblastoma patients. The standard post-operative treatment for newly diagnosed glioblastoma patients is a combination of radiotherapy and temozolomide. TTF devices can be used in conjunction with temozolomide. Available standard therapies for recurrent glioblastoma include nitrosureas, bevacizumab and temozolomide rechallenge, as well as TTF devices. Agents that are being evaluated in clinical trials include novel targeted therapies, novel chemotherapies, and immunotherapies.", "journal": "Expert opinion on pharmacotherapy", "publication_date": "2022-09-21", "doi": "10.1080/14656566.2022.2125302", "authors": [ "Elisa Aquilanti", "Patrick Y Wen" ], "keywords": [ "Lomustine", "Antineoplastic Agents, Alkylating", "Temozolomide", "alkylating agents", "Combined Modality Therapy", "glioblastoma", "newly diagnosed", "clinical trials", "recurrent", "standard of care", "Glioblastoma", "Humans", "Neoplasm Recurrence, Local", "Brain Neoplasms", "Bevacizumab" ] }, { "pmid": "36497413", "title": "Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?", "abstract": "Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration.", "journal": "Cancers", "publication_date": "2022-11-30", "doi": "10.3390/cancers14235932", "authors": [ "Brittany Dewdney", "Lauren Ursich", "Emily V Fletcher", "Terrance G Johns" ], "keywords": [ "calcium signalling", "high-grade glioma", "EGFR", "glioblastoma", "ion channels", "anoctamins" ] }, { "pmid": "35625738", "title": "Looking for the Holy Grail-Drug Candidates for Glioblastoma Multiforme Chemotherapy.", "abstract": "Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a 'breakthrough'. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.", "journal": "Biomedicines", "publication_date": "2022-04-26", "doi": "10.3390/biomedicines10051001", "authors": [ "Beata Pająk" ], "keywords": [ "kinases inhibitors", "glycolysis inhibitors", "clinical trials", "immunomodulatory action", "glioblastoma multiforme (GBM)", "drug candidates" ] }, { "pmid": "34118826", "title": "The impact of the molecular classification of glioblastoma on the interpretation of therapeutic clinical trial results.", "abstract": "In 2016, the World Health Organization (WHO) released the most recent update to the classification of central nervous system tumors. This update has led to the reshaping of tumor identification and subsequently changed current understanding of treatment options for patients. Moreover, the restructuring of the classification of central nervous system tumors to include molecular markers has led to the need to re-evaluate how to interpret pivotal trials. These trials originally enrolled patients purely based upon histologic diagnoses without the use of adjunctive, and frequently diagnostic molecular testing. With this new paradigm also comes the need to assess how one should incorporate molecular markers into current trials as well as shape future trials. First, we will discuss updates on the molecular classification of glioblastoma (GBM) (and its histologic mimics). This will be followed by a review of key pivotal trials which have defined our standard of care for glioblastoma within the context of molecular classification of their study populations. This will be followed by preliminary results of ongoing phase 3 cooperative group trials for high-grade gliomas that were initiated prior to routine molecular classification of tumors and how one could interpret these results in light of advances in molecular classification. Finally, we will end with suggestions for future clinical trial design with a focus on enrollment based upon molecular diagnostics.", "journal": "Chinese clinical oncology", "publication_date": "2021-06-02", "doi": "10.21037/cco-21-33", "authors": [ "Lauren S Singer", "Alexander Z Feldman", "Robin A Buerki", "Craig M Horbinski", "Rimas V Lukas" ], "keywords": [ "clinical trial", "Clinical Trials as Topic", "neuropathology", "IDH", "Astrocytoma", "glioblastoma (GBM)", "Molecular Diagnostic Techniques", "Glioblastoma", "Humans", "Glioma", "Brain Neoplasms", "World Health Organization" ] }, { "pmid": "35561836", "title": "Leveraging the neurosurgical operating room for therapeutic development in NeuroOncology.", "abstract": "Glioblastoma (GBM) remains a disease with a dismal prognosis. For all the hope and promise immunotherapies and molecular targeted therapies have shown for systemic malignancies, these treatments have failed to show any promise in GBM. In this context, the paradigm of investigation of therapeutics for this disease itself must be examined and modifications considered. The unique challenge of the presence of blood-brain and blood-tumor barriers (BBB/BTB) raises questions about both the true levels of systemic drug delivery to the affected tissues. Window-of-opportunity (WoO) trials in neuro-oncology allow for proof-of-concept at the start of a classic phase I-II-III clinical trial progression. For therapeutics that do not have the ability to cross the BBB/BTB, direct delivery into tumor and/or tumor-infiltrated brain in the setting of a surgical procedure can provide a novel route of therapeutic access. These approaches permit neurosurgeons to play a greater role in therapeutic development for brain tumors.", "journal": "Advanced drug delivery reviews", "publication_date": "2022-05-11", "doi": "10.1016/j.addr.2022.114337", "authors": [ "Stephen R Lowe", "Katherine Kunigelis", "Michael A Vogelbaum" ], "keywords": [ "Image guidance", "Blood-Brain Barrier", "Clinical trials", "Operating Rooms", "Drug delivery", "Glioblastoma", "Humans", "Drug Delivery Systems", "Brain Neoplasms" ] }, { "pmid": "33500356", "title": "Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma.", "abstract": "PURPOSE: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. PATIENTS AND METHODS: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. RESULTS: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine-DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. CONCLUSIONS: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "publication_date": "2021-01-26", "doi": "10.1158/1078-0432.CCR-20-3805", "authors": [ "David W Andrews", "Kevin D Judy", "Charles B Scott", "Samantha Garcia", "Larry A Harshyne" ], "keywords": [ "Male", "Adult", "Middle Aged", "Aged", "Receptor, IGF Type 1", "Female", "Glioblastoma", "Humans", "Brain Neoplasms", "Oligodeoxyribonucleotides, Antisense" ] }, { "pmid": "35647354", "title": "Intranasal delivery in glioblastoma treatment: prospective molecular treatment modalities.", "abstract": "Glioblastoma multiforme (GBM) is rare and fatal glioma with limited treatment options. Treatments provide minimal improvement in prognosis and only 6.8% of GBM patients have a life expectancy greater than five years. Surgical resection of this malignant glioma is difficult due to its highly invasive nature and follow-up radiotherapy with concomitant temozolomide, the currently approved standard of care, and will only extend the life of patients by a few months. It has been nearly two decades since the approval of temozolomide and there have been no clinically relevant major breakthroughs since, painting a dismal picture for patients with GBM. Although the future of GBM management seems bleak, there are many new treatment options on the horizon that propose methods of delivery to circumvent current limitations in the standard of care, i.e., the blood brain barrier and treatment resistance mechanisms. The nose is a highly accessible non-invasive route of delivery that has been incorporated into many investigational studies within the past five years and potentially paves the path to a brighter future for the management of GBM. Intranasal administration has its limitations however, as drugs can be degraded and/or fail to reach the site of action. This has prompted many studies for implementation of nanoparticle systems to overcome these limitations and to accurately deliver drugs to the site of action. This review highlights the advances in intranasal therapy delivery and impact of nanotechnology in the management of GBM and discusses potential treatment modalities that show promise for further investigation.", "journal": "Heliyon", "publication_date": "2022-05-22", "doi": "10.1016/j.heliyon.2022.e09517", "authors": [ "Daniel E Morales", "Shaker Mousa" ], "keywords": [ "Blood brain barrier", "Glioblastoma", "Non-invasive", "Intranasal", "Nanotechnology", "Nanoparticles" ] }, { "pmid": "36402744", "title": "Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity.", "abstract": "BACKGROUND: Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. METHODS: We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. RESULTS: Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. CONCLUSIONS: A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.", "journal": "Neuro-oncology", "publication_date": "2023-06", "doi": "10.1093/neuonc/noac253", "authors": [ "Jamie A Dean", "Shyam K Tanguturi", "Daniel Cagney", "Kee-Young Shin", "Gilbert Youssef" ], "keywords": [ "mathematical modeling", "Animals", "Mice", "cell-state plasticity", "clinical trial", "glioblastoma", "Models, Statistical", "radiation oncology", "Dose Fractionation, Radiation", "Glioblastoma", "Humans", "Brain Neoplasms", "Proportional Hazards Models" ] }, { "pmid": "38994929", "title": "Evaluation of the Immunomodulatory Effects of Radiation for Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme.", "abstract": "Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM.", "journal": "Cells", "publication_date": "2024-06-21", "doi": "10.3390/cells13131075", "authors": [ "David Akhavan", "Siddharth Subham", "John D Jeppson", "Brenda Aguilar", "Robyn A Wong" ], "keywords": [ "Animals", "glioblastoma", "radiation", "Glioblastoma", "Humans", "Mice, Inbred C57BL", "Immunotherapy, Adoptive", "Immunomodulation", "c-GAS-STING pathway", "Female", "T-Lymphocytes", "tumor microenvironment", "Receptors, Chimeric Antigen", "CAR T cell therapy", "Cell Line, Tumor", "IL13Rα2", "Mice", "Tumor Microenvironment", "Brain Neoplasms" ] }, { "pmid": "39087397", "title": "Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma.", "abstract": "UNLABELLED: Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis. Genetic inactivation studies to map the signaling network indicated that both S6K1 and S6K2 transmit growth signals in PTEN-deficient GBM. Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM. SIGNIFICANCE: Therapy for glioblastoma would be advanced by incorporating molecularly targeted kinase-directed agents, similar to standard of care strategies in other tumor types. Here, we identify a kinase targeting approach to inhibit the metabolism and growth of glioblastoma.", "journal": "Cancer research communications", "publication_date": "2024-08", "doi": "10.1158/2767-9764.CRC-23-0631", "authors": [ "Catherine A Behrmann", "Kelli N Ennis", "Pranjal Sarma", "Collin Wetzel", "Nicholas A Clark" ], "keywords": [ "Aminopyridines", "Pyrimidines", "Proto-Oncogene Proteins", "Animals", "Ribosomal Protein S6 Kinases, 70-kDa", "Mice", "Axl Receptor Tyrosine Kinase", "Protein Kinase Inhibitors", "Cell Proliferation", "Xenograft Model Antitumor Assays", "Glioblastoma", "Receptor Protein-Tyrosine Kinases", "Humans", "Cell Line, Tumor", "PTEN Phosphohydrolase", "Pyridones", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "39455562", "title": "One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.", "abstract": "Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.", "journal": "Cell death & disease", "publication_date": "2024-10-25", "doi": "10.1038/s41419-024-07170-y", "authors": [ "Kimia Ghannad-Zadeh", "Alyona Ivanova", "Megan Wu", "Taylor M Wilson", "Alyssa Lau" ], "keywords": [ "Dacarbazine", "Animals", "Antineoplastic Agents, Alkylating", "Mice", "Brain Neoplasms", "Cell Proliferation", "Carbon", "Ribonucleotides", "Drug Resistance, Neoplasm", "Glioblastoma", "Humans", "Cell Line, Tumor", "Aminoimidazole Carboxamide", "Purines", "Temozolomide" ] }, { "pmid": "36408162", "title": "Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models.", "abstract": "BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need. METHODS: The aim of this study was to investigate in vitro and in vivo the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM. RESULTS: We showed that ABTL0812 inhibits cell proliferation in a wide panel of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) with half maximal inhibitory concentrations (IC50s) ranging from 15.2 µM to 46.9 µM. Additionally, ABTL0812 decreased GSCs neurosphere formation. GBM cells aggressiveness is associated with a trans-differentiation process towards a less differentiated phenotype known as proneural to mesenchymal transition (PMT). ABTL0812 was shown to revert PMT and induce cell differentiation to a less malignant phenotype in GBM cell lines and GSCs, and consequently reduced cell invasion. As previously shown in other cancer types, we demonstrated that the molecular mechanism of action of ABTL0812 in glioblastoma involves the inhibition of Akt/mTORC1 axis by overexpression of TRIB3, and the activation of endoplasmic reticulum (ER) stress/unfolded protein response (UPR). Both actions converge to induce autophagy-mediated cell death. ABTL0812 anticancer efficacy was studied in vivo using subcutaneous and orthotopic intra-brain xenograft tumor models. We demonstrated that ABTL0812 impairs tumor growth and increases disease-free survival and overall survival of mice. Furthermore, the histological analysis of tumors indicated that ABTL0812 decreases angiogenesis. Finally, we investigated the combination of ABTL0812 with the standard of care treatments for GBM radiotherapy and temozolomide in an orthotopic model, detecting that ABTL0812 potentiates the efficacy of both treatments and that the strongest effect is obtained with the triple combination of ABTL0812+radiotherapy+temozolomide. CONCLUSIONS: Overall, the present study demonstrated the anticancer efficacy of ABTL0812 as single agent and in combination with the GBM standard of care treatments in models of glioblastoma and supports the clinical investigation of ABTL0812 as a potential novel therapy for this aggressive brain tumor type.", "journal": "Frontiers in oncology", "publication_date": "2022-11-02", "doi": "10.3389/fonc.2022.943064", "authors": [ "Andrea Mancini", "Alessandro Colapietro", "Loredana Cristiano", "Alessandra Rossetti", "Vincenzo Mattei" ], "keywords": [ "autophagy", "UPR", "glioblastoma", "ABTL0812", "TRIB3", "Akt", "mTOR", "ER stress" ] }, { "pmid": "40141406", "title": "Understanding Neovascularization in Glioblastoma: Insights from the Current Literature.", "abstract": "Glioblastomas (GBMs), among the most aggressive and resilient brain tumors, characteristically exhibit high angiogenic potential, leading to the formation of a dense yet aberrant vasculature, both morphologically and functionally. With these premises, numerous expectations were initially placed on anti-angiogenic therapies, soon dashed by their limited efficacy in concretely improving patient outcomes. Neovascularization in GBM soon emerged as a complex, dynamic, and heterogeneous process, hard to manage with the classical standard of care. Growing evidence has revealed the existence of numerous non-canonical strategies of angiogenesis, variously exploited by GBM to meet its ever-increasing metabolic demand and differently involved in tumor progression, recurrence, and escape from treatments. In this review, we provide an accurate description of each neovascularization mode encountered in GBM tumors to date, highlighting the molecular players and signaling cascades primarily involved. We also detail the key architectural and functional aspects characteristic of the GBM vascular compartment because of an intricate crosstalk between the different angiogenic networks. Additionally, we explore the repertoire of emerging therapies against GBM that are currently under study, concluding with a question: faced with such a challenging scenario, could combined therapies, tailored to the patient's genetic signatures, represent an effective game changer?", "journal": "International journal of molecular sciences", "publication_date": "2025-03-19", "doi": "10.3390/ijms26062763", "authors": [ "Mariagiovanna Ballato", "Emanuela Germanà", "Gabriele Ricciardi", "Walter Giuseppe Giordano", "Pietro Tralongo" ], "keywords": [ "Animals", "pro-angiogenic factors", "strategies of neovascularization", "Neovascularization, Pathologic", "glioblastoma (GBM)", "Angiogenesis Inhibitors", "aberrant angiogenesis", "Glioblastoma", "emerging therapies", "Humans", "Brain Neoplasms", "Signal Transduction" ] }, { "pmid": "36336899", "title": "Tumor treating fields with radiation for glioblastoma: a narrative review.", "abstract": "BACKGROUND AND OBJECTIVE: With a phase 3 clinical trial (EF-32, ClinicalTrials.gov: NCT04471844) currently underway examining the potential benefit of concurrent chemoradiation and tumor treating fields (TTFields) for patients with glioblastoma (GBM), we present the following narrative review to highlight the current evidence that supports this approach. The current management paradigm for GBM includes maximal safe surgical resection followed by concurrent chemoradiation with further temozolomide (TMZ) and TTFields used as maintenance therapy. Despite several treatment advances over the past few decades, the overall prognosis remains poor and new strategies are currently under investigation, including the use of chemoradiation concurrently with TTFields. METHODS: In this review, we will discuss the preclinical and clinical work that has been performed combining both TTFields with radiation. We performed a narrative review of peer-reviewed articles related to the management of glioblastoma with regard to concurrent chemoradiation and TTFields and synthesized the data in the context of our clinical experience and practice. PubMed, Medline, Embase, Cochrane Library, and various center-specific guidelines were searched for literature regarding concurrent chemoradiation with TTFields for patients with GBM. KEY CONTENT AND FINDINGS: Driven by preclinical studies demonstrating the synergy between TTFields and radiation, more recent clinical work has been performed and has shown that combining treatment is both feasible and tolerable. CONCLUSIONS: In this review, we will discuss the mechanism of action which TTFields and radiation share, as well as discuss the toxicities of combining therapy in patients with GBM. Based on institutional experiences, we will highlight treatment techniques, including scalp sparing methodology and modified computed tomography (CT) simulation workflow, when concurrent TTFields and radiation are given. Lastly, we will provide discuss management considerations, specifically scalp prophylactic interventions and treatments, when using concurrent TTFields with chemoradiation.", "journal": "Chinese clinical oncology", "publication_date": "2022-10", "doi": "10.21037/cco-22-90", "authors": [ "Ryan Miller", "Muneeb Niazi", "Olga Russial", "Spencer Poiset", "Wenyin Shi" ], "keywords": [ "Tumor treating fields (TTFields)", "scalp-sparing radiation", "Antineoplastic Agents, Alkylating", "radiotherapy", "glioblastoma", "Chemoradiotherapy", "Glioblastoma", "Humans", "concurrent therapy", "Brain Neoplasms", "Temozolomide" ] }, { "pmid": "35740330", "title": "Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies.", "abstract": "Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.", "journal": "Biomedicines", "publication_date": "2022-06-02", "doi": "10.3390/biomedicines10061308", "authors": [ "Hyunkoo Kang", "Haksoo Lee", "Dahye Kim", "Byeongsoo Kim", "JiHoon Kang" ], "keywords": [ "glioblastoma", "cancer stem cells", "temozolomide", "chemoresistance" ] } ] }