bims-malgli 2026-05-17 papers

Neuro Oncol. 2026 May 12. pii: noag109. [Epub ahead of print]

Gods do play dice: The activity of regorafenib in glioblastoma not confirmed.

Martin J van den Bent.

Keywords: clinical trial; glioblastoma; regorafenib; screening design

DOI: https://doi.org/10.1093/neuonc/noag109

J Clin Oncol. 2026 May 12. JCO2600444

Lessons From GBM AGILE's Regorafenib Experience in Newly Diagnosed and Recurrent Glioblastoma.

Karla V Ballman.

DOI: https://doi.org/10.1200/JCO-26-00444

Acta Neuropathol Commun. 2026 May 13.

Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation.

Maxim M Bespalov, Vasiliki Gkini, Zeynep Iloglu, Seiya Yamada, Akira Nemoto, Pauliina Filppu, Kalevi Trontti, Liliia Andriichuk, Olli Pietiläinen, Vadim Le Joncour, Anni I Nieminen, Pirjo Laakkonen, Takashi Namba.

Glioblastoma is the most aggressive primary brain tumor in adults, with limited therapeutic success and, therefore, poor prognosis. Its malignancy is partly driven by the high proliferative capacity of glioblastoma cells, yet the underlying molecular mechanisms remain unclear. Recent studies have revealed transcriptomic similarities between glioblastoma cells and human fetal neural stem/progenitor cells (NSCs), suggesting that glioblastoma may exploit developmental programs that promote NSC proliferation. Fetal human NSCs rely on glutaminolysis-a metabolic pathway induced by the human-specific mitochondrial protein ARHGAP11B-to sustain proliferation. Here, we show that ARHGAP11B expression correlates with glioma malignancy and is essential for glioblastoma cell proliferation, implicating a critical role of glutaminolysis in tumor growth. Among glutaminolysis-related enzymes, glutamic-oxaloacetic transaminase 2 (GOT2) shows a strong positive correlation with glioma grade and poor patient prognosis. Functional assays reveal that GOT2 knockdown significantly suppresses glioblastoma cell growth, indicating that GOT2-mediated glutaminolysis is critical for their proliferation. Metabolomic profiling further shows that GOT2 is required for nucleotide precursor synthesis, underscoring its role in supporting DNA replication. Consistently, GOT2 depletion reduces the proportion of glioblastoma cells in the S phase of the cell cycle. These findings suggest glioblastoma cells hijack an evolutionarily adapted metabolic program to support malignant growth.

Keywords: ARHGAP11B; Cell proliferation; GOT2; Glioblastoma; Glutamic-oxaloacetic transaminase; Glutaminolysis; Metabolic reprogramming; Mitochondrial metabolism; Nucleotide biosynthesis; Oncometabolism

DOI: https://doi.org/10.1186/s40478-026-02318-7

Cells. 2026 May 04. pii: 840. [Epub ahead of print]15(9):

Microglia Reprogramming in Glioblastoma: Stem Cell-Derived Factors as Emerging Immunomodulators.

Zahra Amiri, Beatrice Federica Tremonti, Alessandro Corsaro, Alessandra Pattarozzi, Adriana Bajetto, Federica Barbieri, Stefano Thellung, Tullio Florio.

Glioblastoma (GBM) remains one of the most challenging forms of cancer to treat, despite that extensive molecular profiling is now available. Indeed, intratumoral cellular heterogeneity, receptor redundancy, and adaptive resistance through compensatory signaling limit the impact of targeted therapies. Moreover, immunotherapies also underperform: checkpoint blockade and vaccine strategies did not obtain consistent benefits in a low mutational burden, poorly immunogenic tumor microenvironment (TME) dominated by immunosuppressive myeloid cells. In this article, we provide evidence that tumor-associated macrophages (TAMs), a form of CNS resident microglia and infiltrating macrophage, derived from bone marrow, adopt a spatially and transcriptionally distinct, non-binary continuum, shaped by tumor-derived signals and niche constraints, allowing glioma cells to resist to immune and pharmaceutical therapeutics. Metabolic rewiring, including hypoxia-linked glycolytic pressure, lactate signaling, and lipid-associated programs, determine immunosuppressive outputs and restrict plasticity, while epigenetic imprinting (DNA methylation, histone modifications, and chromatin regulators) stabilizes these programs and limits access to inflammatory loci. We discuss how stem cell secretome, and extracellular vesicles (EVs) and their cargo may act as tunable autocrine/paracrine inputs that may bias microglial regulatory control. Finally, we highlight major translational confounders, including EV operational definitions, blood-brain barrier (BBB) permeability and regional exposure, inconsistent dosing units, mixed myeloid compartments, and manufacturing dependent variability. Therefore, an exposure-aware framework that integrates product identity, delivery evidence, state-sensitive potency assays, and functional endpoints would be highly desirable.

Keywords: epigenetic reprogramming; extracellular vesicles; glioblastoma; immunosuppression; metabolic reprogramming; microglia reprogramming; potency assays; stem cell secretome; tumor microenvironment; tumor-associated macrophages

DOI: https://doi.org/10.3390/cells15090840

J Clin Invest. 2026 May 15. pii: e205841. [Epub ahead of print]136(10):

Uncovering a feedback loop in glioblastoma that reinforces stemness and immunosuppression.

Petros Basakis, Ling-Kai Shih, Jiabo Li, Daniel J Brat.

Glioma stem cells (GSCs) are a small subset of self-renewing, plastic, and multipotent neoplastic cells in glioblastoma (GBM) that sit at the apex of a cellular differentiation hierarchy. Elucidating pathways that enhance GSC properties and determine their cell-specific interactions within the immunosuppressive GBM microenvironment are critical for developing effective therapeutic approaches. The CLOCK-BMAL1 complex, which is well known for its activity as a circadian rhythm-regulating transcription factor, plays a critical role in maintaining GSC stemness, and the gene encoding CLOCK was found to be amplified in about 5% of GBM cases. Here, Zhou et al. have uncovered a "symbiotic exclusivity" relationship between CLOCK-BMAL1 and TFPI2, which is also amplified in a small proportion of GBM cases. This relationship forms a HIF-1α/NF-κB P65-mediated positive feedback loop that boosts the proliferative and tumor-enhancing capacities of GSC and immunosuppressive microglia. This self-amplifying regulatory circuit represents an opportunity for intervention to inhibit GBM growth.

DOI: https://doi.org/10.1172/JCI205841

Nat Med. 2026 May 12.

Harnessing the power of biomarkers for diffuse intrinsic pontine gliomas.

Jasia Mahdi.

DOI: https://doi.org/10.1038/s41591-026-04399-2

Nat Cancer. 2026 May 12.

Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase 1 trial.

Glioblastoma is a fatal disease with a median prognosis of 12-18 months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of an open-label, single-arm, phase 1 clinical trial (GT-20) to evaluate the safety and feasibility (primary endpoints) as well as immunogenicity and preliminary clinical activity (secondary endpoints) of GNOS-PV01 monotherapy, a DNA-based personalized therapeutic cancer vaccine administered following surgical resection and radiation for patients with MGMT unmethylated glioblastoma. The GT-20 study vaccinated nine patients, using up to 40 neoantigens per patient (range, 17-40) without causing any serious adverse events, unexpected toxicities or dose-limiting toxicities. The vaccine induced activation and expansion of circulating peripheral T cells in all evaluated patients, except one who was being treated with dexamethasone. The secondary endpoint was to evaluate 6 month progression-free survival and 12 month overall survival; each observed in 66.7% of patients. Median progression-free survival was 8.5 months, median overall survival was 16.3 months and survival at 24 months was 33%, including one long-term survivor still alive 4 years from the time of initial surgery. This study met the pre-specified endpoints and supports the use of GNOS-PV01 as a potentially impactful component of glioblastoma immunotherapy. ClinicalTrials.gov: NCT04015700 .

DOI: https://doi.org/10.1038/s43018-026-01163-w

Cancer Res. 2026 May 12.

Interplay of glioblastoma cells with microglia shape invasive phenotypes during long-distance invasion.

Roland H Friedel, Hongyan Zou.

Glioblastoma (GBM) infiltration poses a formidable therapeutic challenge, but the mechanisms enabling long distance tumor invasion remain poorly defined. In a recent study, Nebeling and colleagues have leveraged longitudinal three-photon intravital microscopy to visualize the migratory behavior of invading GBM cells and their interactions with microglia. Using an immunocompetent autochthonous murine GBM model for live imaging of contralateral cortex and corpus callosum, the team demonstrated that the migration velocity of GBM cells varied by anatomical location, with tumor cells moving faster in corpus callosum than in cortex. Furthermore, GBM cells with less tumor microtubules (TMs) exhibited higher motility and traveled longer distances than TM-rich cells. Interestingly, the authors also uncovered a stage-dependent, biphasic microglial response to invading GBM cells: enhanced surveillance during sparse infiltration, followed by suppressed surveillance as tumor burden increases. Functional analyses identified chemokine receptor CX3CR1 as a key regulator of microglial reactivity and a requirement of microglia to drive GBM invasiveness. These findings align with earlier evidence that spatial constraints and microglial organization influence GBM invasion. Together, these works highlight a critical role of microglia and the tumor microenvironment in shaping invasive GBM phenotypes and offer new avenues for therapeutic strategies to limit GBM invasion.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-2075

J Clin Oncol. 2026 May 12. JCO2600461

Balancing Risk, Benefit, and Reality: Navigating Early Phase Studies in Pediatric Diffuse Midline Glioma.

Jordan R Hansford, Neevika Manoharan, Sara Khan, Rachel Chon, Keith Desserich, Mark W Kieran, David D Eisenstat.

DOI: https://doi.org/10.1200/JCO-26-00461