bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–07–06
nine papers selected by
Oltea Sampetrean, Keio University
  1. Assessing time-trend bias in glioblastoma prognosis over two decades of clinical trials.
  2. Malignant Transformation of Glioblastoma: One Step at a Time.
  3. Individualizing glioma radiotherapy planning by optimization of a data and physics-informed discrete loss.
  4. Final Report on NCCTG N0877 (Alliance): A Phase II Randomized, Placebo-Controlled Trial of Chemoradiotherapy with or without Dasatinib for Glioblastoma.
  5. Metagenomics and transcriptomics analysis of aspartame's impact on gut microbiota and glioblastoma progression in a mouse model.
  6. Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.
  7. Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma.
  8. New microRNA-based therapies reveal common targets in paediatric medulloblastoma and adult glioblastoma.
  9. Mesothelin is a surface antigen present on human meningioma and can be effectively targeted by CAR T-cells.
  1. Neuro Oncol. 2025 Jun 28. pii: noaf158. [Epub ahead of print]
    Assessing time-trend bias in glioblastoma prognosis over two decades of clinical trials.
    Giacomo Sferruzza, Karthik Desingu, Andrés Cubero Cruz, Gaetano Finocchiaro.
       BACKGROUND: The time-trend bias represents a potential limitation in the use of external controls in glioblastoma (GBM) trials. In this study, we assessed whether outcomes for newly diagnosed GBM (ndGBM) patients treated with the standard Stupp protocol in clinical trials have changed over the past two decades.
    METHODS: We retrieved individual patient survival pseudo-data from Stupp protocol arms reported in trials published over the last twenty years. Survival distributions were approximated using Weibull distributions, and an Accelerated Failure Time (AFT) model was used to evaluate any potential time trend by correcting for identified key prognostic factors.
    RESULTS: MGMT methylation status and Karnofsky Performance Status emerged as the main determinants of survival differences among clinical trials. Both in a multivariable regression that included all candidate prognostic factors and after adjustment for the main determinants, publication year showed no impact on the outcome of the Stuppprotocol control arms. The performance of the model was validated using three independent Phase 3 cohorts, providing additional evidence for the absence of time-trend bias.
    CONCLUSIONS: No evidence of time-trend bias was observed in Phase 3 GBM trials over the past two decades once major prognostic factors were accounted for.
    Keywords:  Stupp protocol; glioblastoma; historical controls; time-trend bias
    DOI:  https://doi.org/10.1093/neuonc/noaf158
  2. Cancer Discov. 2025 Jul 03. 15(7): 1312-1314
    Malignant Transformation of Glioblastoma: One Step at a Time.
    John J Y Lee, Mario L Suvà.
      In this issue of Cancer Discovery, Kim and colleagues characterize the transcriptional and epigenomic changes associated with gradual transformation of murine subventricular zone neural stem cells into glioblastoma, identifying an intermediary precancerous stage. Analysis of human glioblastoma and tumor-free subventricular zone tissues hints at the presence of precancerous cells with transcriptional similarity to murine precancerous cells and distinct aneuploidy from the bulk tumor. See related article by Kim et al., p. 1377.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0698
  3. Nat Commun. 2025 Jul 01. 16(1): 5982
    Individualizing glioma radiotherapy planning by optimization of a data and physics-informed discrete loss.
    Michal Balcerak, Jonas Weidner, Petr Karnakov, Ivan Ezhov, Sergey Litvinov, Petros Koumoutsakos, Tamaz Amiranashvili, Ray Zirui Zhang, John S Lowengrub, Igor Yakushev, Benedikt Wiestler, Bjoern Menze.
      Brain tumor growth is unique to each glioma patient and extends beyond what is visible in imaging scans, infiltrating surrounding brain tissue. Understanding these hidden patient-specific progressions is essential for effective therapies. Current treatment plans for brain tumors, such as radiotherapy, typically involve delineating a uniform margin around the visible tumor on pre-treatment scans to target this invisible tumor growth. This "one size fits all" approach is derived from population studies and often fails to account for the nuances of individual patient conditions. We present the Glioma Optimizing the Discrete Loss (GliODIL) framework, which infers the full spatial distribution of tumor cell concentration from available multi-modal imaging, leveraging a Fisher-Kolmogorov type physics model to describe tumor growth. This is achieved through the newly introduced method of Optimizing the Discrete Loss (ODIL), where both data and physics-based constraints are softly assimilated into the solution. Our test dataset comprises 152 glioblastoma patients with pre-treatment imaging and post-treatment follow-ups for tumor recurrence monitoring. By blending data-driven techniques with physics-based constraints, GliODIL enhances recurrence prediction in radiotherapy planning, challenging traditional uniform margins and strict adherence to the Fisher-Kolmogorov partial differential equation model, which is adapted for complex cases.
    DOI:  https://doi.org/10.1038/s41467-025-60366-4
  4. Neuro Oncol. 2025 Jun 28. pii: noaf156. [Epub ahead of print]
    Final Report on NCCTG N0877 (Alliance): A Phase II Randomized, Placebo-Controlled Trial of Chemoradiotherapy with or without Dasatinib for Glioblastoma.
    William G Breen, J G Dixon, S K Anderson, J N Sarkaria, P D Brown, E S Yan, S Kizilbash, E Galanis, Daniel Anderson, David Tran, Miroslaw Mazurczak, Derek R Johnson, F J Geoffroy, Clinton Leinweber, N N Laack.
       BACKGROUND: Dasatinib is an oral inhibitor of the Src kinase family, with preclinical data indicating impact on gliomagenesis, tumor invasion, and radiosensitivity.
    METHODS: NCCTG N0877 is a phase 1 dose escalation and phase II randomized study evaluating the maximum tolerated dose (MTD), safety, and efficacy of dasatinib with radiation and temozolomide (TMZ) for glioblastoma. Following identification of the MTD, adult patients with a histologic diagnosis of glioblastoma were randomized 2:1 between dasatinib given with standard concurrent and adjuvant TMZ, versus placebo with standard concurrent and adjuvant TMZ. Radiation dose was 60 Gy in 30 fractions. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), toxicity, and quality of life.
    RESULTS: Thirteen patients were enrolled on the phase I component and established the MTD and phase II dose of 150 mg given daily. A total of 204 patients were enrolled on the phase II component. OS was not different between arms (median OS 15.6 months for dasatinib compared to 19.3 months for placebo, hazard ratio:1.21 favoring placebo, 95% CI: 0.88-1.65, logrank p-value: 0.238). Similarly, PFS was not significantly different between dasatinib and placebo arms. There was significantly increased anemia, nausea, and creatinine elevation with dasatinib, but significantly more grade 3 lymphopenia with placebo.
    CONCLUSIONS: The addition of dasatinib to standard chemoradiation did not improve outcomes for patients with glioblastoma.
    Keywords:  Glioblastoma; chemotherapy; clinical trial; radiotherapy
    DOI:  https://doi.org/10.1093/neuonc/noaf156
  5. Sci Rep. 2025 Jul 02. 15(1): 23298
    Metagenomics and transcriptomics analysis of aspartame's impact on gut microbiota and glioblastoma progression in a mouse model.
    Kaikai Meng, Yi Bao, Ganlin Chen, Junru Qu, Shuaiyi Liang, Sanqi An, Yang Chen, Xinli Liu, Xuanjian Fu.
      Aspartame, a widely used artificial sweetener, has been extensively studied for its potential health effects. Emerging evidence suggests that aspartame intake may directly impact the composition and function of the intestinal microbiota, which could subsequently influence the risk, progression, and treatment of glioblastoma multiforme (GBM) within the tumor microenvironment. However, it remains unclear whether aspartame intake affects intestinal flora, gene expression, and epigenetic regulation during tumor progression. To address these gaps in knowledge, we conducted a comprehensive metagenomics and transcriptomics analysis of aspartame's impact on gut microbiota and glioblastoma progression in a mouse model. Using a well-established mouse model and a rigorous metagenomics and transcriptomics approach, our results demonstrated that although the aspartame diet did not significantly affect tumor growth, it induced changes in the composition of the gut microbiota, particularly a decrease in the relative abundance of the Rikenellaceae family. Additionally, key N6-methyladenosine (m6A)-regulated genes, such as cyclin-dependent kinase inhibitor 1A (CDKN1A), MYC (myelocytomatosis) oncogene, and transforming growth factor-β (TGFB1), were significantly upregulated in GBM tumors exposed to aspartame. Notably, the expression of TGFB1 (transforming growth factor-β) suggested a critical role in the progression of GBM mediated by aspartame-induced m6A modifications. Our integrative analysis offered novel perspectives on the intricate interplay between dietary aspartame intake, gut microbiota, and tumor biology.
    Keywords:  Aspartame; Glioblastoma; Metagenomics; N6-methyladenosine; RNA
    DOI:  https://doi.org/10.1038/s41598-025-06193-5
  6. Acta Neuropathol Commun. 2025 06 28. 13(1): 143
    Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.
    Benjamin Lin, Abigail K Shelton, Erin Smithberger, Julia Ziebro, Kasey R Skinner, Ryan E Bash, Richard Kirkman, Allie Stamper, Madison Butler, Alex Flores, Steven P Angus, Michael P East, Timothy F Cloughesy, David A Nathanson, Michael E Berens, Jann N Sarkaria, Zev A Binder, Donald M O'Rourke, Timothy C Howton, Brittany N Lasseigne, Christopher D Willey, Gary L Johnson, Anita B Hjelmeland, Frank B Furnari, C Ryan Miller.
      GBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM. Upfront combinatorial therapy featuring EGFR tyrosine kinase inhibitors (TKI) may overcome these challenges. To identify combinatorial drug targets within the kinome, we temporally characterized drug-induced kinome rewiring in isogenic, genetically engineered Cdkn2a-deleted mouse astrocytes expressing human EGFRvIII. We utilize RNA sequencing and multiplex inhibitor beads, coupled with mass spectrometry, to demonstrate that kinome rewiring exhibits both shared and unique kinases after acquired resistance develops to EGFR TKI, despite using models with a common genetic background. Additionally, we noted that kinases altered in the acute setting are distinct from those in acquired resistance. By identifying kinome vulnerabilities throughout the acute, dynamic drug response process, we generated a kinase signature associated with EGFR inhibition. Further molecular interrogation of signature genes revealed that drug treatment induces an unexpected increase in Cdk6 protein, but not mRNA, despite live cell imaging and transcriptomic evidence indicating decreased proliferation. Survival experiments with orthotopic allografts show that upfront combination inhibition of Cdk6, using abemaciclib, and EGFR, using neratinib, significantly prolonged median survival compared to neratinib alone. Our findings suggest that identifying and inhibiting targets with synthetic lethality in the upfront combinatorial setting is a viable approach for precision oncology and may help provide an avenue to overcome the resistance mechanisms that contributed to the failures of EGFR as a molecular target in GBM.
    Keywords:  EGFR; Glioblastoma; Kin­ome rewiring; Synthetic lethality; Upfront combinatorial therapy
    DOI:  https://doi.org/10.1186/s40478-025-02068-y
  7. Clin Cancer Res. 2025 Jul 01.
    Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma.
    Rachael A Vaubel, Wenjuan Zhang, Ju-Hee Oh, Ann C Mladek, Tugce I Pasa, Jennifer K Gantchev, Katie L Waller, Gerard Baquer, Sylwia A Stopka, Michael S Regan, Md Amin Hossain, Paul A Decker, Matthew L Kosel, Shiv K Gupta, Sonia Jain, Paige P Sarkaria, Zeng Hu, Lauren L Ott, Brett L Carlson, Katrina K Bakken, Surabhi Talele, Wenqiu Zhang, Keith L Ligon, Eudocia Q Lee, Jeanette E Eckel Passow, Danielle M Burgenske, Nathalie Y R Agar, William F Elmquist, Jann N Sarkaria.
       BACKGROUND: Navtemadlin is a potent small molecule inhibitor of MDM2, which has completed a Phase 0 window of opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient derived xenografts (PDXs).
    METHODS: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples.
    RESULTS: In vitro, navtemadlin showed robust on-target activity in TP53 wild-typeGBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX, compared to 100 mg/kg in a non-amplified PDX. CNS distribution was limited by blood-brain barrier efflux (Kp_brain=0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood-brain barrier efflux (Rag-/-Abcb1a-/- Abcg2-/-), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in 3 (of 16) tumor samples from phase 0 study patients at the 240 mg dose level.
    CONCLUSION: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-0244
  8. Sci Rep. 2025 Jul 02. 15(1): 23044
    New microRNA-based therapies reveal common targets in paediatric medulloblastoma and adult glioblastoma.
    Denis Mustafov, Laura Thomas, Shoib S Siddiqui, George I Lambrou, Maria Braoudaki.
      Medulloblastoma (MB), the most prevalent brain malignancy in children, presents significant challenges in paediatric oncology due to its aggressiveness and potential for relapse. Tailored treatments are crucial to mitigate treatment-related toxicities and long-term side effects on developing brains. Our study aimed to identify therapeutic targets for paediatric MB and explore common miRNA biosignatures with glioblastoma (GB), the most aggressive adult brain tumour. High-throughput small-RNA sequencing identified miR-206 and miR-383 as highly downregulated in MB samples, suggesting their tumour suppressor properties. Bioinformatics analysis identified CORO1C and SV2B as their targets. RT-qPCR, western blotting, and immunohistochemistry confirmed their overexpression in MB and GB. Elevated CORO1C expression was also found in adult MB and GB tissue samples. The role of both miRNAs on their target genes was validated through in vitro functional assays. Our study uncovers the potential role of miR-206/CORO1C and miR-383/SV2B axes as innovative therapeutic targets for combating aggressive paediatric and adult brain malignancies.
    DOI:  https://doi.org/10.1038/s41598-025-05517-9
  9. Neuro Oncol. 2025 Jun 28. pii: noaf155. [Epub ahead of print]
    Mesothelin is a surface antigen present on human meningioma and can be effectively targeted by CAR T-cells.
    Rishab Ramapriyan, Fred G Barker, Leland G Richardson, Jing Sun, Gust Vandecandelaere, Jane M Shim, Guillaume De Vlaminck, Matthew Gaffey, Eric P Grewal, Masih Tazhibi, Kourosh Morshedy, Amir R Aref, Syeda M Batool, Xiaopeng Guo, Nazanin Ijad, Leonora Balaj, Hiroaki Wakimoto, Maria Martinez-Lage, Matthew J Frigault, Mark B Leick, Joshua D Bernstock, Wenya Linda Bi, Bob S Carter, E Antonio Chiocca, Jorg Dietrich, Elizabeth R Gerstner, Genevieve M Boland, Brian V Nahed, Scott R Plotkin, Russell W Jenkins, Priscilla K Brastianos, William T Curry, Marcela V Maus, Bryan D Choi.
       BACKGROUND: Meningioma is the most common primary CNS tumor, with high-grade cases exhibiting aggressive behavior, frequent recurrence, and poor prognosis. Currently, no systemic therapies are approved for recurrent or malignant meningiomas. Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in hematologic malignancies and promise for solid tumors but its use for meningiomas has been underexplored. Mesothelin, a glycoprotein overexpressed in several solid tumors of mesodermal origin, may serve as a viable immunotherapeutic target. This study aimed to evaluate mesothelin as a CAR T-cell target in meningiomas.
    METHODS: Mesothelin expression was analyzed in patient-derived meningioma samples using immunohistochemistry, flow cytometry, and droplet digital PCR. Mesothelin-specific CAR T-cells were generated and evaluated in vitro, ex vivo using patient-derived organotypic tumor spheroids (PDOTS), and in vivo using orthotopic meningioma mouse models of human xenografts. Cytotoxicity, T-cell proliferation, cytokine secretion, and tumor clearance were assessed.
    RESULTS: Mesothelin was detected in a subset of tumors across all meningioma grades at the transcript and protein levels, with surface expression confirmed in patient-derived primary cells. Mesothelin-specific CAR T-cells exhibited potent and specific cytotoxicity, T-cell activation, and cytokine secretion in vitro and effectively eliminated PDOTS. In orthotopic human xenograft models, mesothelin CAR T-cell therapy led to significant tumor regression and prolonged survival.
    CONCLUSIONS: Mesothelin is a viable CAR T-cell target for meningiomas, and mesothelin-specific CAR T-cell therapy shows strong preclinical efficacy. These findings provide a rationale for early-phase clinical trials of mesothelin CAR T-cell therapy in patients with refractory meningiomas.
    Keywords:  CAR T-Cell therapy; brain neoplasms; immunotherapy; meningioma; mesothelin
    DOI:  https://doi.org/10.1093/neuonc/noaf155
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