bims-malgli 2026-10-25 papers

Issue of 2026–10–25
five papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2026 Oct 19. pii: noag238. [Epub ahead of print]

Biomarker-guided treatment strategies for patients with gliomas in clinical practice.

Emilie Le Rhun, Ingo K Mellinghoff, Tobias Weiss, Marian C Neidert, Wolfgang Wick, Michael Weller.

Targeted therapy has made important contributions to improving outcomes for patients with many solid tumors, but has had only limited activity so far in patients with gliomas, notably glioblastoma. Failure of targeted therapy in glioblastoma is likely due to redundance of oncogenic pathway activation and so far the inability to identify suitable targets and apply biomarker-based enrichment strategies in clinical trial designs. In contrast, in non-glioblastoma tumors, there are promising developments which have already changed clinical practice: inhibition of mutant isocitrate dehydrogenase (IDH) exemplified by vorasidenib, the first approved drug specifically for IDH-mutant gliomas, has changed the landscape for targeted therapy of WHO grade 2 gliomas. Furthermore, dordaviprone, an antagonist of dopamine receptor D2/3 (DRD2/3) and an allosteric agonist of the mitochondrial protease caseinolytic mitochondrial matrix peptidase proteolytic subunit (ClpP), emerges as a potentially active agent in patients with recurrent K27M-mutant diffuse midline gliomas. Finally, BRAF mutations, neurotrophic tyrosine receptor kinase ( r fibroblast growth factor receptor (FGFR) gene fusions continue to raise interest as therapeutic targets at least for subsets of patients with gliomas. Almost no targeted therapy approaches for ependymomas have emerged. Improved clinical trial designs including shared control arms early on and using pharmacodynamic endpoints ideally in enriched patient populations are the path forward towards the identification of further active treatments for patients with gliomas.

Keywords: diffuse; glioblastoma; histone; midline; pathway; sequencing; signaling

DOI: https://doi.org/10.1093/neuonc/noag238

Neuro Oncol. 2026 Oct 22. pii: noag266. [Epub ahead of print]

EGFRvIII-Positive Glioblastoma: Structural Rewiring, Immune Microenvironmental Remodeling, and Therapeutic Resistance.

Haoyuan Ye, Jinming Qiu, Fangge Zhu, Rong Quan, Wenting Su, Renxi Wang, Yi Fu.

Glioblastoma (GBM) harboring EGFRvIII represents a biologically distinct and highly aggressive tumor subset characterized by aberrant receptor signaling, marked intratumoral heterogeneity, and profound immune remodeling. Rather than acting as a constitutively active truncated receptor, EGFRvIII represents a structurally rewired EGFR variant whose altered extracellular architecture, receptor assembly, and trafficking promote ligand-independent signaling and signaling plasticity, thereby supporting tumor proliferation, stemness, invasion, and angiogenesis. Beyond tumor-intrinsic effects, EGFRvIII also contributes to the formation of a spatially heterogeneous, myeloid-dominant and immunosuppressive tumor microenvironment, characterized by myeloid-cell expansion, impaired T cell effector function, and mesenchymal-like tumor-immune plasticity. Despite extensive therapeutic efforts including tyrosine kinase inhibitors, monoclonal antibodies, vaccines, immune checkpoint blockade, and EGFRvIII-targeted CAR-T cell strategies, durable clinical efficacy remains limited by the interplay of antigen heterogeneity, adaptive signaling, clonal evolution, and microenvironmental immunosuppression. Taken together, EGFRvIII can be viewed as a structural and evolutionary regulator that links receptor rewiring and signaling plasticity with immune ecosystem remodeling and therapeutic resistance, underscoring the need for integrated strategies that target both tumor cell-intrinsic signaling and the suppressive microenvironment.

Keywords: EGFRvIII; Glioblastoma; immunotherapy resistance; myeloid immunosuppression; structural biology

DOI: https://doi.org/10.1093/neuonc/noag266

Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2616218123

Multi-omics and spatial analysis of microgravity-grown glioblastoma organoids reveal superior modeling of advanced disease after long-term spaceflight.

Alice Burchett Darantiere, Maksym Zarodniuk, Shelby Giza, Jason Rexroat, Paul Kuehl, Twyman Clements, Keerthiveena Balraj, Haley Marco, Alura D'Souza, Julian Najera, Rohit Bhargava, Meenal Datta.

Creating accurate organoid models remains a challenge, particularly for diseases like glioblastoma (GBM), an aggressive, treatment-resistant brain cancer with an immunosuppressive microenvironment. To overcome limitations of Earth-based models (sedimentation and disaggregation) and leverage the unique advantages of space (accelerated disease progression and immune dysregulation), this study utilizes a panel of GBM-myeloid organoids cultured for 40 d aboard the International Space Station. Spaceflight-grown GBM organoids have more uniform morphology compared to ground controls. We observed a context-dependent response to spaceflight, with the inclusion of macrophages and monocytes altering the bulk and spatial transcriptional response. While GBM-alone organoids have transcriptional markers of less aggressive disease in microgravity, organoids containing GBM cells + monocytes have increased expression of genes associated with disease progression and poor patient outcomes. Gene expression patterns are more spatially organized, with mesenchymal-related genes enriched in the core and inflammation-related genes enriched at the periphery, mimicking GBM tumor architecture. Microgravity-grown GBM+monocyte organoids exhibit increased secretion of proteins such as CXCL12 and LOX-1, associated with more aggressive disease. Infrared chemical imaging confirms spatial chemical gradients of DNA, protein, and lipid species in both space- and terrestrially-grown organoids. In summary, this work presents not only an advanced model of glioblastoma for basic and translational research but also demonstrates methods to acquire diverse data from organoids compatible with the unique constraints of in-space systems, helping establish a working model for orbital oncology.

Keywords: International Space Station; immune-tumoroids; immunosuppression; spatial transcriptomics; tumor-associated macrophages

DOI: https://doi.org/10.1073/pnas.2616218123

Cancer Res. 2026 Oct 22.

PHGDH Sustains Oncometabolite Production to Drive Resistance to Mutant IDH Inhibition in Glioma that can be Monitored by Metabolic Imaging.

Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Joanna J Phillips, Jennie W Taylor, Pavithra Viswanath.

Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and prolongs progression-free survival in some, but not all, patients. Here, using patient-derived models, genetically engineered glioma cells, orthotopic xenografts, and patient tissue, we showed that phosphoglycerate dehydrogenase (PHGDH) mediates intrinsic resistance to vorasidenib by sustaining D-2HG production despite IDHm inhibition. Silencing PHGDH suppressed residual D-2HG synthesis and restored vorasidenib sensitivity in resistant models, whereas PHGDH overexpression restored D-2HG production and induced resistance in sensitive models. Importantly, restoration of intracellular D-2HG rescued growth despite continued vorasidenib treatment, demonstrating a causal role for residual D-2HG production in the resistant phenotype. Mechanistically, a permissive chromatin state characterized by increased H3K4me3, reduced H3K27me3, and enhanced ATF4 occupancy at the PHGDH promoter facilitated PHGDH upregulation in resistant models. Pharmacologic induction of this chromatin state induced PHGDH expression, restored D-2HG production, and conferred resistance to vorasidenib in sensitive models. Consistently, tumor tissue from patients with poor response to IDHm inhibitor treatment exhibited higher PHGDH expression, coupled with the ATF4-enriched permissive chromatin state observed in resistant models. Finally, deuterium metabolic imaging of D-2HG production from diethyl-[3,3'-2H]-α-KG provided an early, non-invasive readout of response and resistance to vorasidenib in vivo. Collectively, this study identifies a chromatin-regulated ATF4-PHGDH-D-2HG axis as a mechanism of intrinsic resistance to IDHm inhibition and establishes diethyl-[3,3'-2H]-α-KG as a metabolic imaging probe for interrogating treatment response in IDHm gliomas.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4071