bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–01–04
eight papers selected by
Oltea Sampetrean, Keio University
  1. Multimodality mapping of immunotherapy distribution as a predictive marker in glioma.
  2. Correction to 'SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD'.
  3. Combinatorial treatment of glioblastoma with temozolomide (TMZ) plus 5-ethynyl-2'-deoxyuridine (EdU).
  4. VITA-GBM: EPIC-0502-Driven HIF1α Degradation Overcomes Bevacizumab Resistance and Synergizes with TMZ in Glioblastoma.
  5. Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels.
  6. Phase 1 study of mebendazole therapy for refractory/progressive or recurrent pediatric brain tumors.
  7. Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans.
  8. Cellular reprogramming of H3K27M pediatric high-grade glioma to neuron-like state.
  1. Neuro Oncol. 2025 Dec 31. pii: noaf295. [Epub ahead of print]
    Multimodality mapping of immunotherapy distribution as a predictive marker in glioma.
    Jonas G Scheck, Berin Boztepe, Julius M Kernbach, Kianush Karimian-Jazi, Lennart Heinz, Katharina Schregel, Volker Sturm, Marianne Schell, Jovana Bojcevski, Manuel Fischer, Rosa Eurich, Isabel Poschke, Julius Schwarz, Dennis A Agardy, Simone Jünger, Christian Schulz, Ferdinand Althammer, Alexander R Osidach, Amir Abdollahi, Lukas Bunse, Varun Venkataramani, Stefan M Pfister, Frank Winkler, Tobias Kessler, Wolfgang Wick, Sabine Heiland, Michael Platten, Christopher Rodell, Martin Bendszus, Ina Weidenfeld, Michael O Breckwoldt.
       BACKGROUND: Scarce T cell infiltration, immunosuppressive tumor-associated macrophages and ineffective drug delivery drive glioma progression and limit treatment efficacy. Mapping immunotherapy distribution by multimodality imaging might be a biomarker that could aid tumor monitoring and guide therapy development.
    METHODS: To assess drug delivery, we developed a MRI-lightsheet microscopy platform (MR-LSM) to monitor immunotherapy at the cellular level in two immunocompetent glioma models (Gl261, SB28). The atezolizumab (PD-L1 inhibitor) subgroup of the multicenter N2M2/NOA20 trial in MGMT unmethylated GBM patients was assessed by CNN analysis and correlated to progression free survival.
    RESULTS: In contrast to the conventional Gl261 glioma model, SB28 gliomas are characterized by poor immunogenicity and resistance to Toll-like receptor (TLR) 7 targeted therapy delivered by CDNP-R848 nanoparticles. SB28 resistance is driven by microvascular pathology, vasogenic edema and drug off-targeting to peritumoral edema and white matter tracts. Vascular endothelial growth factor (VEGF) inhibition in conjunction with irradiation and dual immunotherapy (DIR) targeting innate (CDNP-R848) and adaptive immunity (anti-CTLA-4) breaks resistance, increases survival and reverses drug off-targeting. Mechanistically, tumor control is orchestrated by vascular normalization, enhanced CD8+ T cell influx and a proinflammatory shift of myeloid cells along with strong IL-12/IL-13 upregulation. In a translational analysis of the multicenter N2M2/NOA20 trial we validate that edema and microvascular pathology are associated with poor prognosis in glioblastoma patients treated with checkpoint immunotherapy and that patients without edema have increased PFS.
    CONCLUSIONS: We develop a customizable imaging platform to map drug delivery to glioma with broad applicability in neuroscience and neurooncology.
    Keywords:  blood-brain barrier disruption; drug distribution; glioma; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noaf295
  2. Clin Transl Med. 2026 Jan;16(1): e70559
    Correction to 'SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD'.
      
    DOI:  https://doi.org/10.1002/ctm2.70559
  3. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2532187123
    Combinatorial treatment of glioblastoma with temozolomide (TMZ) plus 5-ethynyl-2'-deoxyuridine (EdU).
    Humeyra Kaanoglu, Yasemin K Akyel, Adebimpe Adefolaju, Alain Valdivia, Dominique Higgins, Rani S Sellers, Caroline Mosely, Corey J Haswell, William C Zamboni, Shawn D Hingtgen, Andrew B Satterlee, Aziz Sancar.
      Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with incidence peaking in later life. It is commonly treated with surgery followed by administration of ionizing radiation and the DNA-alkylating agent temozolomide (TMZ). Even though this regimen confers some progression-free survival, there is essentially no cure with the median survival with the standard of care being about 12 mo. Currently, several alternative approaches are being developed to improve upon this outcome. We have already shown EdU alone effectively treats GBM, and we now study the efficacy of TMZ+EdU combination therapy. TMZ+EdU significantly improves antitumor efficacy compared to either single-agent therapy against GBM cell lines in vitro, against three different orthotopic GBM xenograft models, and against passage-zero GBM patient tumor tissues engrafted within an organotypic brain slice culture-based platform. Together, our results suggest that EdU could be effective alongside standard-of-care TMZ in patients with GBM.
    Keywords:  5-ethynyl-2′-deoxyuridine (EdU); anticancer drugs; chemotherapy; glioblastoma (GBM); temozolomide (TMZ)
    DOI:  https://doi.org/10.1073/pnas.2532187123
  4. Neuro Oncol. 2025 Dec 31. pii: noaf293. [Epub ahead of print]
    VITA-GBM: EPIC-0502-Driven HIF1α Degradation Overcomes Bevacizumab Resistance and Synergizes with TMZ in Glioblastoma.
    Yaqing Ding, Qi Zhan, Longtao Cui, Xiaoteng Cui, Yilin Zhao, Qixue Wang, Biao Hong, Yanping Huang, Dongyuan Su, Chunchao Cheng, Hanyi Xu, Siwen Liang, Xun Zhao, Yuhao Liu, Chunsheng Kang.
       BACKGROUND: Glioblastoma (GBM) is characterized by extensive tissue hypoxia. This hypoxic microenvironment drives chemoresistance and promotes aberrant vascularization, critically limiting the efficacy of temozolomide (TMZ) and bevacizumab (BEV). Here, we report EPIC-0502, a novel small-molecule competitive antagonist that inhibits hypoxia signaling while sensitizing GBM to both TMZ and BEV.
    METHODS: EPIC-0502 was identified through molecular dynamics simulation. Its target blocking effect was validated via non-targeted metabolomics, stable isotope tracing-based metabolic flux analysis, and pull-down assays. The mechanisms underlying EPIC-0502 activity were elucidated by Western Blot (WB), Co-Immunoprecipitation (Co-IP), ELISA, Seahorse assays, and Immunofluorescence (IF). The sensitizing effects of EPIC-0502 on TMZ and BEV were evaluated in orthotopic GBM models.
    RESULTS: EPIC-0502 inhibited α-ketoglutarate (α-KG) to succinate conversion, depleting cytoplasmic succinate levels and inhibiting phosphoglycerate kinase 1 (PGK1) succinylation and phosphorylation, which significantly attenuated glycolysis. Furthermore, EPIC-0502 destabilized HIF1α by promoting hydroxylation-dependent ubiquitination, while impairing its transcriptional activity. Through HIF1α degradation, EPIC-0502 enhanced GBM sensitivity to TMZ via E2F1 downregulation and reversed hypoxia-induced vascular endothelial growth factor A (VEGFA) overexpression, potentiating the antiangiogenic efficacy of BEV. Collectively, these actions enable EPIC-0502 to synergistically enhance the therapeutic efficacy of TMZ/BEV combination.
    CONCLUSION: Based on EPIC-0502-driven HIF1α degradation that overcomes BEV resistance and synergizes with TMZ, we propose the novel VITA-GBM regimen comprising: Vascular targeting (BEV), Inhibition of hypoxia signaling (EPIC-0502), TMZ chemotherapy, and Alignment of synergistic mechanisms. This strategy enhances the efficacy of first-line therapies and provides a promising approach to improve overall survival in GBM patients.
    Keywords:  Bevacizumab; Glioblastoma; HIF1α; TMZ sensitization; protein succinylation
    DOI:  https://doi.org/10.1093/neuonc/noaf293
  5. J Clin Invest. 2026 Jan 02. pii: e192599. [Epub ahead of print]136(1):
    Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels.
    Fanen Yuan, Xujia Wu, Huairui Yuan, Donghai Wang, Tengfei Huang, Po Zhang, Hailong Mi, Weichi Wu, Suchet Taori, Priscilla Chan, Kenji Miki, Maged T Ghoche, Linjie Zhao, Kalil G Abdullah, Steve A Kay, Qiulian Wu, Jeremy N Rich.
      Cuproptosis involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron-sulfur cluster proteins, leading to cell death. Pharmacologic induction of cuproptosis has been proposed as a cancer therapy. Here, we find that glioblastoma (GBM) stem cells (GSCs) displayed relative resistance to cuproptosis with circadian variation of intracellular copper levels. CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase copper transporting alpha (ATP7A). Circadian control of copper homeostasis was mediated by the core clock transcription factor, brain and muscle ARNT-like 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back into the circadian circuitry through sequestosome 1/p62-mediated lysosomal degradation of BMAL1. Targeting the circadian clock or fatty acid desaturation augmented cuproptosis antitumor effects. Crosstalk between the core circadian clock and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance, which may inform development of combination therapies for GBM.
    Keywords:  Brain cancer; Cell biology; Neuroscience; Oncology; Stem Cells
    DOI:  https://doi.org/10.1172/JCI192599
  6. Neurooncol Pract. 2025 Dec;12(6): 1092-1098
    Phase 1 study of mebendazole therapy for refractory/progressive or recurrent pediatric brain tumors.
    Paul Phan, Stacie L Stapleton, Gregory J Riggins, Michael A Koldobskiy, Eric Raabe, Kenneth J Cohen.
       Background: Mebendazole (MBZ) is an anti-helminthic that has shown antitumor activity in mice with gliomas and subsequently in medulloblastoma models. Safety and tolerability have been demonstrated in adults with brain tumors but not explored in children as a monotherapy. We characterized the safety and maximum tolerated dose of oral MBZ in pediatric patients with refractory or progressive brain tumors and assessed progression-free survival (PFS) as a secondary objective.
    Methods: Patients up to 21 years of age with refractory or progressive brain tumors were enrolled at 2 centers in a 3 + 3 design with 3 doses of MBZ (1250, 1875, or 2500 mg/m2/day). MBZ was taken orally 3 times per day and continued until there were signs of toxicity or clinical/radiographic progression. Safety and tolerability were analyzed with descriptive statistics.
    Results: There were 17 patients enrolled between 2017 and 2022 with diffuse intrinsic pontine gliomas, high-grade astrocytomas, diffuse midline gliomas, glioblastoma multiform, ependymoma, and nonspecific gliomas. At all 3 dose levels, MBZ was well-tolerated with no dose-limiting toxicities. 121 adverse events (AE) including 69 AEs possibly/probably related to MBZ occurred-the most common being decreased lymphocyte count (n = 6). Six grade 3 (anorexia, dehydration, hypokalemia, increased GGT, blood bilirubin increased, and aspartate aminotransferase increased) and 1 grade 4 (vomiting) were reported. The mean PFS was 7.6 weeks (range of 2 to 24 weeks).
    Conclusions: MBZ is safe and tolerable in treating refractory or progressive pediatric brain tumors, with doses up to 2500 mg/m2/day. There was limited evidence of single-agent efficacy.
    Keywords:  brain tumors; mebendazole; pediatric; phase 1
    DOI:  https://doi.org/10.1093/nop/npaf060
  7. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2513172122
    Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans.
    Maksym Zarodniuk, Anna Wenninger, Julian Najera, Jihaeng Lee, Jack Markillie, Cameron MacKenzie, Jenny Bergqvist-Patzke, Bianca Batista, Megna Panchbhavi, R'nld Rumbach, Alice Burchett, Charles Sander, Meenal Datta, Christopher Patzke.
      Mass effect, characterized by the compression and deformation of neural tissue from space-occupying lesions, can lead to debilitating neurological symptoms and poses a significant clinical challenge. In the primary brain tumor glioblastoma (GBM), we have shown previously that compressive solid stress originating from the growing tumor reduces cerebral blood flow, leading to neuronal loss, increased functional impairment, and poor clinical outcomes. However, the direct effects of compression on neurons and the underlying biophysical mechanisms are poorly understood. Here, using multiscale compression systems and physiologically relevant in vitro and in vivo models, we find that chronic mechanical compression induces neuronal apoptosis and loss of synaptic puncta, leading to disrupted neural network activity, as assessed by calcium imaging. This is accompanied by increased HIF-1 signaling and upregulation of downstream stress-adaptive genes in neurons. We further show that chronic compression triggers AP-1-driven gene expression in glial cells, promoting a neuroinflammatory response. Together, these findings reveal that solid stress directly contributes to neuronal dysfunction and inflammation caused by GBM by activating distinct pathways that can be targeted in future studies for neuroprotection.
    Keywords:  glioblastoma; gliosis; hypoxia; solid stress
    DOI:  https://doi.org/10.1073/pnas.2513172122
  8. Acta Neuropathol Commun. 2025 Dec 30.
    Cellular reprogramming of H3K27M pediatric high-grade glioma to neuron-like state.
    Abicumaran Uthamacumaran, Cynthia Horth, Eric Bareke, Michel Gravel, Jacek Majewski.
      This study explores the cell fate reprogrammability of H3K27M-mutant pediatric high-grade gliomas (pHGG) using neuronal transdifferentiation as a potential targeted therapy. We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures. In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition. This study demonstrates that pHGGs can be phenotypically redirected toward neuronal-like identities through modulating cell fate differentiation programs. These findings advance the concept of 'differentiation therapy' as a promising intervention to reduce phenotypic plasticity and malignancy in pHGG ecosystems. While these are early in vitro findings, the potential ability to steer and control glioma cells toward stable, less malignant fates offers promising translational potential for patient-centered targeted therapies.
    Keywords:  Cell fate control; Differentiation therapy; Glioma; Neurons; Pediatric cancers; Phenotypic plasticity; Precision oncology
    DOI:  https://doi.org/10.1186/s40478-025-02185-8
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