bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–05–10
seven papers selected by
Oltea Sampetrean, Keio University
  1. A comprehensive clinical, molecular, radiological, and surgical analysis for predicting prognosis in IDH-mutant astrocytoma patients.
  2. Immune Subtypes and Survival in Patients with Primary Glioma.
  3. Phase separation of TRNAU1AP protein sustains selenoprotein translation and promotes glioblastoma tumorigenesis.
  4. Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.
  5. Molecular modulators of CDK4/6 inhibitor response in experimental glioma identified through genome-wide CRISPR-Cas9 screening.
  6. Androgen loss accelerates brain tumour growth via HPA axis activation.
  7. lncRNA in EGFR‑driven glioblastoma.
  1. Neuro Oncol. 2026 May 02. pii: noag096. [Epub ahead of print]
    A comprehensive clinical, molecular, radiological, and surgical analysis for predicting prognosis in IDH-mutant astrocytoma patients.
    Minjee Cho, Minjin Kim, Hyeonjin Kim, Kaeum Choi, Kyunghwa Han, Sung Soo Ahn, Hong In Yoon, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee, Yae Won Park, Whitney B Pope.
       BACKGROUND: To comprehensively investigate clinical, molecular, radiological, and surgical factors for prediction of progression-free survival (PFS) in patients with isocitrate dehydrogenase (IDH)-mutant astrocytomas.
    METHODS: A total of 210 patients with newly diagnosed WHO grade 2 to 4 IDH-mutant astrocytomas between 2005 and 2023 were included. Clinical, molecular, radiological, and surgical factors were evaluated. Total, contrast-enhancing, non-enhancing, and necrotic tumor volumes were quantified via automatic volumetric segmentation (cm3). Significant predictors of PFS were identified using univariable and multivariable Cox analyses.
    RESULTS: The median PFS was 106.8 months, with a 5-year PFS rate of 67.5%. On multivariable analysis, higher initial KPS (hazard ratio [HR] = 0.76, P = .029) remained as a favorable predictor of PFS, while higher WHO grade (grade 3, HR = 1.01, P = .997; grade 4, HR = 2.91, P = .013; reference standard as grade 2, overall P = .032), larger total tumor volume (HR = 1.03, P = .013), and lesser extent of resection (EOR) (subtotal resection, HR = 1.80, P = .043; partial resection, HR = 2.14, P = .014; biopsy, HR = 3.79, P = .008; reference standard as gross total resection, overall P = .015) remained as unfavorable predictors of PFS. Age and MGMT promoter methylation were not significant predictors, while the adverse prognostic impact of WHO grade was primarily driven by WHO grade 4 tumors.
    CONCLUSIONS: Our work presents a detailed analysis of a large series of IDH-mutant astrocytomas, underscoring the prognostic importance of WHO grade 4, tumor volume, and EOR.
    Keywords:  IDH-mutant Astrocytoma; Magnetic Resonance Imaging; Predictive Model; Progression-free Survival
    DOI:  https://doi.org/10.1093/neuonc/noag096
  2. medRxiv. 2026 Apr 30. pii: 2026.04.29.26351981. [Epub ahead of print]
    Immune Subtypes and Survival in Patients with Primary Glioma.
    Yu Fang, Jiwoong Kim, Zachary J Thompson, Youngchul Kim, Harshan Ravi, Asim Mazin, Carlos M Moran Segura, Jonathan V Nguyen, Robert J Macaulay, Filippo Veglia, Reid C Thompson, Sajeel A Chowdhary, Kathleen M Egan, Natarajan Raghunand.
       Background: Gliomas are heterogeneous tumors with poor outcomes following current therapies, including immunotherapy. The tumor microenvironment (TME) is a critical determinant of therapeutic response in gliomas. We have classified the immune TME of gliomas by multiplex immunofluorescence (mIF).
    Methods: Tissue taken at initial resection from 354 patients with newly-diagnosed glioma grades 2-4 were analyzed using three mIF panels of markers for T, B, and myeloid cells. Tumor cores were characterized by the relative abundances of: (i) 15 primary immune phenotypes, (ii) 96 secondary immune phenotypes, and, (iii) 29 biologically meaningful multi-marker immune phenotypes.
    Results: Using unsupervised cluster analysis of WHO grade 4 gliomas we identified four subtypes α, β, γ, and δ that were internally reproducible. Immune subtype α was characterized by high abundance of antigen-presenting cells (APCs) and low levels of MHC II- monocytes. Subtype β was high in regulatory T cells and myeloid cells, but low in lymphocytes with effector functions. Subtype γ displayed high abundance of immune cell phenotypes, particularly lymphocytes with effector or helper functions. Subtype δ was low in lymphoid and myeloid immune phenotypes and APCs, with poorer outcomes. Grade 3 tumors could also be classified into α, β, γ, and δ subtypes, indicating generalizability of these immune TME subtypes across high grade gliomas.
    Conclusions: We have identified internally reproducible criteria for classifying gliomas according to the immune microenvironment, findings that could aid our understanding of the natural progression of low- and high-grade gliomas and inform the rational application of immune-oncologic therapeutic interventions.
    DOI:  https://doi.org/10.64898/2026.04.29.26351981
  3. Neuro Oncol. 2026 May 02. pii: noag097. [Epub ahead of print]
    Phase separation of TRNAU1AP protein sustains selenoprotein translation and promotes glioblastoma tumorigenesis.
    Xiaowei Zhang, Li Li, Linlin Li, Shijun Yu, Taohui Ouyang, Xiao Han, Richard I Joh, Yiwen Chen, Huizhi Wang, Suyun Huang.
       BACKGROUND: Glioblastoma (GBM) depends on selenoproteins, yet the mechanisms underlying their dysregulation remain poorly understood. The tRNA-binding protein TRNAU1AP also remains largely uncharacterized, with its mechanistic functions in in vivo tumorigenesis undefined. Additionally, while IGF2BP3 is the most dysregulated m6A reader in GBM, the pathways through which it promotes glioblastoma stem cell (GSC) self-renewal have yet to be elucidated.
    METHODS: TRNAU1AP expression in human GBMs and public datasets was analyzed by Western blotting, immunohistochemistry, and gene expression profiling. Functions of TRNAU1AP in GSCs were evaluated through gain- and loss-of-function assays assessing proliferation, self-renewal, and tumorigenicity. Proteomics, spatial transcriptomics, RNA immunoprecipitation, and polysome profiling were employed to investigate TRNAU1AP-mediated regulation of selenoprotein synthesis. RNA immunoprecipitation and phase-separation assays were used to characterize the TRNAU1AP-EEFSEC interaction. Multi-omics and RNA stability analyses were performed to elucidate IGF2BP3-dependent regulation of TRNAU1AP expression.
    RESULTS: TRNAU1AP is essential for the proliferation, stemness, and tumorigenesis of GSCs and is associated with poor patient survival. TRNAU1AP interacts with EEFSEC to form a phase-separated complex that enhances EEFSEC binding to sec-tRNAsec, thereby promoting the translation of several selenoproteins. These selenoproteins act as key effectors mediating the oncogenic functions of TRNAU1AP. Furthermore, IGF2BP3 upregulates TRNAU1AP expression through m⁶A-dependent transcript stabilization, leading to increased selenoprotein synthesis and enhanced GSC stemness and tumorigenic potential.
    CONCLUSION: These findings establish novel oncogenic roles of TRNAU1AP, and reveal that IGF2BP3-TRNAU1AP coupling constitutes an important mechanism for the selenoprotein synthesis and for gliomagenesis, thereby advancing the understanding of RNA-binding proteins in cancer biology.
    Keywords:  Glioblastoma stem cells; Phase separation; Selenoproteins; TRNAU1AP; m6A
    DOI:  https://doi.org/10.1093/neuonc/noag097
  4. JCI Insight. 2026 May 05. pii: e198298. [Epub ahead of print]
    Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.
    Jesse A Coker, Steven R Martinez, Sang Hoon Han, Anthony R Sloan, Amit Kumar Gupta, George Bukenya, Paul Polzer, James H Ramos, Emma G Rico, Annabella Rico, A Abigail Lindsey, Tanvi Navadgi, Natalie Reitz, Todd Romigh, Jonathan Macdonald, Dhiraj Sonawane, Christopher M Goins, Christopher G Hubert, Nancy S Wang, Feixiong Cheng, Joseph Alvarado, Samuel A Sprowls, Justin D Lathia, Shaun R Stauffer.
      Glioblastoma (GBM) cancer stem cells (CSCs) contribute to tumor recurrence, treatment resistance, and dismal clinical outcomes. Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a novel series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our novel WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify novel combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.
    Keywords:  Brain cancer; Cell biology; Neuroscience; Oncology; Structural biology; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.198298
  5. Neuro Oncol. 2026 May 04. pii: noag093. [Epub ahead of print]
    Molecular modulators of CDK4/6 inhibitor response in experimental glioma identified through genome-wide CRISPR-Cas9 screening.
    Surender Surender, Lara Annina Haeusser, Laurence Kuhlburger, Foteini Tsiami, Nihal Olcay Dogan, Louise Maise, Sven Nahnsen, Susanne Beck, Daniel Josef Merk, Ghazaleh Tabatabai.
       BACKGROUND: Glioblastoma harbors frequent alterations in the retinoblastoma (RB1) pathway, providing a genetic rationale for therapeutic targeting with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The NOA-20 trial did not reveal a progression-free survival benefit of CDK4/6 inhibition plus radiation therapy in newly diagnosed, MGMT-unmethylated glioblastoma. In fact, CDK4/6 inhibitor monotherapy has not demonstrated efficacy in solid tumors. We aimed at discovering response modulators to CDK4/6 inhibition, paving the way for rational combination therapies.
    METHODS: We conducted genome-wide CRISPR-Cas9 screens in human glioma cell lines and stem-like cells (LN229, LN18, LNZ308, T98G, and GS-9) under CDK4/6 inhibition, employing knockout (Brunello library) and activation strategies (Calabrese library), followed by genetic and pharmacological validation of selected candidate genes in vitro and ex vivo (primary cultures) as well as the investigation of one functionally-instructed combination therapy in vivo.
    RESULTS: Loss of AMBRA1 and gain of function of CCNE1 reduced sensitivity to CDK4/6 inhibition in glioma cells, whereas disruption of CHEK1 or FAM122A resulted in synthetic lethality in combination with CDK4/6 inhibition. AMBRA1-deficient glioma cells exhibited increased sensitivity to CHK1 inhibition, revealing a context-specific vulnerability. Combined inhibition of CHK1 and CDK4/6 led to synergistic anti-glioma activity in vitro, ex vivo, and in vivo.
    CONCLUSIONS: Our data identify AMBRA1, CCNE1, CHEK1, and FAM122A as potential molecular modifiers of CDK4/6 inhibition response in experimental glioma and provide a biological rationale for combinatorial targeting with CDK4/6 inhibition in glioblastoma.
    Keywords:   AMBRA1 ; CHEK1 ; Glioblastoma; abemaciclib; functional genomics
    DOI:  https://doi.org/10.1093/neuonc/noag093
  6. Nature. 2026 May 06.
    Androgen loss accelerates brain tumour growth via HPA axis activation.
    Juyeun Lee, Yoon-Mi Chung, Daniel J Silver, Yue Hao, Dylan Scott Lykke Harwood, Alyssa Ealy, Amanda M Serapiglia, Lee Curtin, Julia R Benedetti, Christine Ann Pittman Ballard, Kamya Lapsley, Andrea Alvarez-Vazquez, Jessica Goldberg, Cathy Li, Sehaj Kaur, Rian Neal, Sabrina Z Wang, Kristen E Kay, Josephine Volovetz, Ellen S Hong, R'ay Fodor, Jakub Jarmula, Michael Nicosia, Joshua B Rubin, Kristin R Swanson, Quinn T Ostrom, Nikhil Panicker, Bjarne Winther Kristensen, Michael Berens, Nima Sharifi, Justin D Lathia.
      Many cancers, including glioblastoma (GBM), show a male-biased incidence and associated worse outcomes1. The mechanisms that underlie this sex difference remain unclear but may involve an immune response2 that is partly driven by sex hormones such as androgens. Such hormones are thought to suppress antitumour T cell immunity and to promote tumour progression3,4. However, here we report a previously unreported tumour-suppressive role for androgens in brain tumours. Using mouse models, we demonstrate that androgen loss via castration accelerates intracranial tumour growth, whereas the opposite effect (delayed tumour growth) is observed in extracranial tumours. Similar effects were observed in male patients with GBM, in whom testosterone treatment significantly reduced the risk of death. In male mice with GBM tumours, castration-induced systemic T cell dysfunction driven by increased levels of serum glucocorticoids, which act on myeloid cells to promote an immunosuppressive tumour microenvironment. Mechanistically, hyperactivation of the hypothalamus-pituitary-adrenal axis in castrated mice with GBM is driven by increased neuroinflammatory signalling through IL-1β and TNF. Spatial transcriptomic analysis further revealed that androgen loss enhances inflammasome activation in microglia, which promotes this neuroinflammatory state. Together, our findings demonstrate that brain tumours drive distinct neuroinflammatory and neuroendocrine pathways in the androgen-deprived setting and highlight organ-specific regulation of antitumour immunity.
    DOI:  https://doi.org/10.1038/s41586-026-10451-5
  7. Nat Cell Biol. 2026 May 06.
    lncRNA in EGFR‑driven glioblastoma.
    Andrew Dhawan, Justin D Lathia.
      
    DOI:  https://doi.org/10.1038/s41556-026-01947-3
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒16 at 23:00.