bims-malgli 2026-03-29 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–03–29
seven papers selected by
Oltea Sampetrean, Keio University

Repurposing T-type calcium channel blocker Lomerizine as a therapeutic strategy for glioblastoma.
A Deep Learning-Driven Framework Integrating Organoid-Based Functional Validation Identifies Universal Neoantigens from Recurrent Glioma Mutations.
CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination.
RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy.
Nexus of IDO1/Kynurenine Pathway to T-Cell Exhaustion: Hypoxia-Induced Tryptophan Metabolism in Glioblastoma.
Recent progress and future directions to advance glioblastoma research: A consensus perspective from the 2024 Christopher Davidson Forum.
An EGFR co-amplified lncRNA HELDR promotes glioblastoma malignancy through KAT7-driven gene programs.

JCI Insight. 2026 Mar 24. pii: e182522. [Epub ahead of print]

Repurposing T-type calcium channel blocker Lomerizine as a therapeutic strategy for glioblastoma.

Toshiya Ichinose, Sho Tamai, Nozomi Hirai, Takashi Maejima, Kosuke Nambu, Hemragul Sabit, Shingo Tanaka, Masashi Kinoshita, Masahiko Kobayashi, Michihiro Mieda, Atsushi Hirao, Mitsutoshi Nakada.

  Glioblastoma (GBM) is the most malignant primary brain tumor. The presence of glioma stem/initiating cells (GICs) is known to cause strong treatment resistance; therefore, GICs are a major target for GBM therapy, although there are no therapies targeting GICs clinically. To identify novel treatments for GBMs, we performed drug repositioning screening using GICs and identified T-type calcium channel blocker lomerizine-a migraine prophylactic drug. Lomerizine inhibited proliferation, migration, invasion, and cell cycle progression and induced apoptosis in GICs and differentiated glioma cells. Lomerizine had antitumor effects by inactivating STAT3 in all cell lines. Furthermore, lomerizine also dephosphorylated AKT and ERK only in GICs and strong tumor suppressive ability. Lomerizine also reduced tumor volume and prolonged overall survival in vivo. Based on our data from in vitro and in vivo experiments, lomerizine has potential as a novel GBM therapeutic agent targeting against both GICs and differentiated glioma cells and could benefit for GBM patients.

Keywords:  Brain cancer; Cell biology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.182522
Cancer Res. 2026 Mar 26.

A Deep Learning-Driven Framework Integrating Organoid-Based Functional Validation Identifies Universal Neoantigens from Recurrent Glioma Mutations.

Chen Wang, Ting Sun, Yufei He, Mingchen Yu, Chang-Qing Pan, Huimin Hu, Yishuo Sun, Di Wang, Zhongliang Cui, Jiazheng Zhang, You Zhai, Zhongfang Shi, Ziwei Li, Menghui Xu, Young Taek Oh, Tao Jiang, Zhiyuan Xu, Guanzhang Li, Jing Zhang, Wei Zhang.

Glioblastoma (GBM) is the most common malignant intracranial tumor in adults, with a median survival of only 16-20 months. Neoantigen therapy has shown advantages in the treatment of GBM, as it improves the immunosuppressive microenvironment within the tumor. However, the identification of truly immunogenic neoantigens remains a major challenge. Current computational prediction tools primarily focus on antigen presentation, while algorithms that incorporate T cell immunogenicity features remain limited. Furthermore, standard validation methods, such as ELISpot assays, lack physiological relevance and do not fully recapitulate the tumor microenvironment. Here, we developed a neoantigen prediction algorithm, TCRscore, based on publicly available datasets by integrating human leucocyte antigen binding and T-cell receptor (TCR) recognition features. Twenty-one patient-derived glioblastoma organoid models were established from isocitrate dehydrogenase wildtype tumors to validate performance of the algorithm. Predicted neoantigens were evaluated using ELISpot assays, flow cytometry, and in vitro killing assays based on organoid-T cell co-culture systems. TCRscore outperformed six existing tools in predicting immunogenic neoepitopes. The organoid models retained the key histological and transcriptomic features of parental tumors and provided an effective platform for functional validation. Co-culture assays confirmed that neoantigen-specific T cells could induce targeted killing in GBM organoids. In particular, the analysis identified that the recurrent PIK3R1G376R mutation contributed to a potential shared neoantigen in glioblastoma. Overall, by integrating TCRscore with organoid-based validation, this study provides a high-fidelity, high-quality GBM neoantigen database with significantly enhanced prediction accuracy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2679
Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2602460123

CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination.

Ruhi Polara, Briony L Gliddon, Raja Ganesan, Lorena T Davies, John Toubia, Sakthi Lenin, Ghizal Siddiqui, Olivia Morris-Hanon, Melinda N Tea, Paul A B Moretti, Dung A Nguyen, Chung Hoow Kok, Chloe Shard, Alexander H Staudacher, Michael P Brown, Darren J Creek, Guillermo A Gomez, Daniel Thomas, Stuart M Pitson, Nirmal Robinson.

  CD47 is an innate immune checkpoint that inhibits phagocytosis by myeloid cells, contributing to immune evasion by cancer cells. CD47-blocking antibodies have limited efficacy in glioblastoma (GBM), and the cell-intrinsic role of CD47 is poorly understood. In this study, we show that CD47 is highly expressed at the invasive edge of GBM tumors, and its elevated expression correlates with poor patient survival. We demonstrate that CD47 loss impairs GBM cell proliferation, migration, and invasion, independent of immune activity, and leads to reduced tumor burden and prolonged survival in vivo. Our study identifies ROBO2 signaling as a key downstream effector of CD47 and demonstrates that loss of ROBO2 similarly reduces GBM cell proliferation and migration. Importantly, we have uncovered that CD47 stabilizes ROBO2 by sequestering the E3 ubiquitin ligase ITCH, thereby blocking ubiquitination and proteasomal degradation of ROBO2. These findings establish CD47 as a key regulator of GBM cell plasticity and highlight the therapeutic potential of targeting CD47-ROBO2 signaling in GBM.

Keywords:  CD47; ITCH; ROBO2; glioblastoma; ubiquitin

DOI:  https://doi.org/10.1073/pnas.2602460123
Nat Commun. 2026 Mar 23.

RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy.

Min Mao, Hang Ji, Wen-Qian Yu, Qu-Jing Gai, Qiang Sun, Qian Yan, Sen-Lin Xu, Meng-Li Zhu, Mei-Hua Qu, Han-Min Liu, Jean-Philipe Hugnot, Xi He, Xin Wang, Yan Wang.

Glioblastoma (GBM) remains a lethal brain tumor due to therapy resistance. While autophagy contributes to temozolomide (TMZ) resistance, its regulation is incompletely understood. This study investigates the role of replication factor RFC4, which is associated with poor prognosis and TMZ resistance in GBM. Multi-omics analyses and molecular experiments reveal that TMZ-induced chromatin accessibility enables transcription factor YY1 to bind the RFC4 promoter and upregulate its expression. RFC4, in turn, stabilizes the kinase STK38, which is essential for autophagosome formation. The RFC4-STK38 interaction facilitates BECN1 recruitment, thereby activating autophagy. Phosphorylation of STK38 at T444 stabilizes this complex, whereas a phospho-deficient mutant impairs autophagy. In vivo, RFC4 overexpression confers TMZ resistance, reversible by autophagy inhibition. Thus, our findings identify the RFC4-STK38-BECN1 axis as a mechanism underlying TMZ resistance and a potential target for precision therapy in GBM.

DOI: https://doi.org/10.1038/s41467-026-70798-1
Metabolites. 2026 Mar 10. pii: 185. [Epub ahead of print]16(3):

Nexus of IDO1/Kynurenine Pathway to T-Cell Exhaustion: Hypoxia-Induced Tryptophan Metabolism in Glioblastoma.

Matthew Abikenari, George Nageeb, Joseph H Ha, Matthew Adam Sjoholm, Justin Liu, Brandon Bergsneider, Jocelyn Valenzuela, James Poe, Kwang Bog Cho, Rohit Verma, Caren Wu, Vivek Sanker, Ravi Medikonda, Lily H Kim, John Choi, Matei A Banu, Michael Lim.

  Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan-kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity.

Keywords:  GCN2–AHR signaling; IDO1/TDO2; glioblastoma; hypoxia (HIF-1α/HIF-2α); immunometabolism; metabolic reprogramming; precision immunotherapy; spatial transcriptomics; tryptophan–kynurenine pathway; tumor microenvironment

DOI:  https://doi.org/10.3390/metabo16030185
Neuro Oncol. 2026 Mar 23. pii: noag043. [Epub ahead of print]

Recent progress and future directions to advance glioblastoma research: A consensus perspective from the 2024 Christopher Davidson Forum.

Christopher Davidson Forum Investigators

  This position paper from the 2024 Christopher Davidson Forum held at WashU Medicine in Saint Louis provides a comprehensive consensus on scientific advances, key challenges, and future directions in glioblastoma (GBM) research. A multidisciplinary group of over 130 academic neuro-oncology professionals discussed recent developments and existing gaps in understanding the complex tumor biology of GBM tumors, characterizing and overcoming the resistance of GBM to immunotherapeutic approaches, defining tumor-brain interactions and their functional consequences for tumor progression and therapy resistance, and developing and clinically translating novel neuro- and nanotechnologies. We conclude with a call to action for researchers and clinicians in the neuro-oncology field to address fundamental gaps in our understanding of GBM tumor, immune, and neurobiology, and develop critical infrastructure to more rapidly translate novel therapeutic paradigms into the clinic through multi-disciplinary and cross-institutional collaborations.

Keywords:  Glioblastoma; cancer neuroscience; neuro-nanotechnology; translational neuro-oncology; tumor immunology

DOI:  https://doi.org/10.1093/neuonc/noag043
Nat Cell Biol. 2026 Mar 27.

An EGFR co-amplified lncRNA HELDR promotes glioblastoma malignancy through KAT7-driven gene programs.

Xiaozhou Yu, Xiao Song, Richard A Schäfer, Qingshu Meng, Deanna Tiek, Runxin Wu, Qiu He, Maya Walker, Qi Cao, Rendong Yang, Bo Hu, Shi-Yuan Cheng.

EGFR amplification frequently occurs within extrachromosomal DNAs (ecDNAs) and is the most prevalent mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments has been unsuccessful. Here we show a long non-coding RNA (lncRNA) that is co-amplified with EGFR, which we name hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-selective lncRNA that promotes tumorigenicity independent of EGFR signalling. HELDR exhibits widespread chromatin association and recruits the transcription co-activator p300 to the KAT7 promoter. p300-induced H3K27ac at the KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac and H4K12ac that activate KAT7-driven gene programmes that are critical for GBM malignancy. Targeting KAT7 or HELDR markedly enhances therapeutic effects of anti-EGFR treatments for GBM. These results not only reveal the role of HELDR in EGFR-amplified GBM but also provide a strong rationale to characterize the role of lncRNAs co-amplified with driver oncogenes in human cancers.

DOI: https://doi.org/10.1038/s41556-026-01924-w