bims-malgli 2025-10-26 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–10–26
seven papers selected by
Oltea Sampetrean, Keio University

Dordaviprone: First Approval.
Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid cells.
Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.
Cytokine CCL2 secreted by cancer-associated fibroblasts augments temozolomide resistance in glioblastoma through ERK1/2 signaling.
HRH1-targeting mAb: a precision therapeutic strategy for Glioblastoma.
Spatial immune profiling defines a subset of human gliomas with functional tertiary lymphoid structures.
Targeting immunosuppressive myeloid cells via implant-mediated slow release of small molecules to prevent glioblastoma recurrence.

Drugs. 2025 Oct 25.

Dordaviprone: First Approval.

Hannah A Blair.

Dordaviprone (MODEYSO™) is a protease activator being developed by Chimerix for the treatment of various cancers, including glioma, glioblastoma, endometrial cancer, ovarian cancer, acute myeloid leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndrome and colorectal cancer. On 6 August 2025, dordaviprone received accelerated approval in the USA for the treatment of adult and paediatric patients 1 year of age and older with diffuse midline glioma harbouring an H3 K27M mutation with progressive disease following prior therapy. This article summarizes the milestones in the development of dordaviprone leading to this first approval for glioma.

DOI: https://doi.org/10.1007/s40265-025-02252-3
Sci Rep. 2025 Oct 21. 15(1): 36804

Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid cells.

Golnaz Asaadi Tehrani, Rebecca N Kubick, Maksym Zarodniuk, Meenal Datta.

  Histone deacetylase inhibitors (HDACis) are promising anti-cancer agents but remain underexplored in glioblastoma (GBM). This study evaluated the effects of three HDACis-CAY10603, vorinostat (SAHA), and valproic acid (VPA)-on human GBM cell lines (U87, MGG8) with immortalized human astrocytes (IHAs) as healthy controls. HDACis were tested alone or in combination with temozolomide (TMZ), the standard chemotherapy for GBM, in both 2D (monolayer) and 3D (neurosphere) cultures. Additionally, co-culture of GBM cells with macrophages (M0, biochemically differentiated from THP-1 human monocytes) was used to examine the impact of HDACis on cancer-immune interactions. Results demonstrated that all three HDACis significantly reduced cell viability and synergistically enhanced the effect of TMZ. CAY10603 and SAHA induced early apoptosis and upregulated caspase 3 (CASP3) expression, whereas VPA primarily induced late apoptosis and necrosis in GBM cultures. VPA induced both G0/G1 and G2/M cell cycle arrest, while SAHA and CAY10603 only induced G2/M arrest. mRNA expression analysis following HDACi treatment in U87 neurospheres revealed that HDACis inhibited expression of markers for epithelial-to-mesenchymal transition (EMT), proliferation, and stemness pathways. In U87-M0 co-cultures, we observed significant upregulation of stemness markers and the pro-inflammatory cytokine TNF-α following CAY10603 and VPA treatments. In contrast, TMZ monotherapy upregulated the expression of the immunosuppressive cytokine TGF-[Formula: see text]. These findings suggest that HDAC inhibition-including the novel small molecule CAY10603-sensitizes GBM to temozolomide and confers potent anti-tumor effects that combat GBM (e.g., reducing proliferation, EMT, stemness). Among the HDAC inhibitors tested, CAY10603 exhibited the most potent anti-tumor effect in 3D neurosphere and macrophage co-culture models, significantly enhancing apoptosis and disrupting pro-tumorigenic and anti-inflammatory signaling in GBM. Our in vitro findings -e.g., with 3D neurospheres that better mimic physiological tumor growth than 2D monolayers-warrant future in vivo testing of HDACis alone or in combination with chemotherapy.

Keywords:  Chemotherapy resistance; HDAC; Macrophages; Neurospheres; Suberoylanilide hydroamic acid; Valproic acid

DOI:  https://doi.org/10.1038/s41598-025-20749-5
Neuro Oncol. 2025 Oct 25. pii: noaf248. [Epub ahead of print]

Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.

Milan R Savani, Mohamad El Shami, Kenji Miki, Lauren C Gattie, Bailey C Smith, William H Hicks, Jacob O Weiss, Skyler S Oken, Lavanya N Katta, Tracey Shipman, Maged T Ghoche, Lauren G Zacharias, Misty S Martin-Sandoval, Eric Y Montgomery, Yi Xiao, Diana D Shi, Jeremy N Rich, Timothy E Richardson, Pascal O Zinn, Bradley C Lega, Thomas P Mathews, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

   BACKGROUND: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk.
METHODS: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities.
RESULTS: HPLM culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic GDP-mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells.
CONCLUSIONS: We present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.

Keywords:  Glioma; metabolism; organoids; preclinical models; stable isotope tracing

DOI:  https://doi.org/10.1093/neuonc/noaf248
Oncogene. 2025 Oct 24.

Cytokine CCL2 secreted by cancer-associated fibroblasts augments temozolomide resistance in glioblastoma through ERK1/2 signaling.

Mingrong Zuo, Shuxin Zhang, Siliang Chen, Yuze He, Junhong Li, Yufan Xiang, Yunbo Yuan, Tengfei Li, Wanchun Yang, Zhihao Wang, Wenhao Li, Ni Chen, Yuan Yang, Yunhui Zeng, Qing Mao, Mina Chen, Yanhui Liu.

The intricate tumor microenvironment largely influences chemoresistance in glioblastoma. Cancer-associated fibroblasts (CAFs) that modulate tumor progression have recently been identified as non-tumor stromal cells within the glioblastoma microenvironment. It remains unclear whether CAFs play a role in conferring chemoresistance to glioblastoma. The effects and mechanisms of CAFs on glioblastoma cells under temozolomide (TMZ) treatment are investigated by a series of patient-derived CAFs, orthotopic xenograft mouse models, and glioblastoma organoids (GBOs). Patient-derived cells have a transcriptomic and biomolecular profile of CAFs. CAFs promote temozolomide resistance in glioblastoma in vitro; these findings are consistent with results from intracranial tumor xenografts and GBO models. Mechanistically, CAFs express and secrete a significantly higher C-C motif chemokine ligand 2 (CCL2), which selectively enhances the activation of the ERK1/2 signaling in glioblastoma cells. Pharmacologically disrupting the CCL2-CCR2 axis or MEK1/2-ERK1/2 pathway effectively restores the therapeutic efficacy of temozolomide in glioblastoma cells and patient-derived GBOs. The decreased phosphor-ERK1/2 expression induced by trametinib treatment is also observed in glioblastoma cells following the CCL2-CCR2 axis inhibition. The present study suggests that targeting the CCL2/CCR2/ERK1/2 pathway may help overcome chemoresistance in glioblastomas caused by CAFs.

DOI: https://doi.org/10.1038/s41388-025-03601-y
Oncogene. 2025 Oct 23.

HRH1-targeting mAb: a precision therapeutic strategy for Glioblastoma.

Kankai Wang, Peiqi Zhao, Xiaohong Zhu, Fan Tang, Hong Chen, Ying Zhang, Hao Wang, Yu Chen, Yuanbo Pan, Qichuan Zhuge, Jianjing Yang.

Glioblastoma multiforme (GBM) remains one of the most aggressive primary brain tumors with limited therapeutic options. The efficacy of standard temozolomide chemotherapy is critically influenced by O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. While monoclonal antibody (mAb)-based biologics represent a promising therapeutic approach, current clinical trials have failed to demonstrate significant improvement in overall patient survival. In this study, systematic screening identified histamine H1 receptor (HRH1) as a potential therapeutic target. Genetic silencing of HRH1 significantly inhibited GBM cell proliferation, migration, and invasion both in vitro and in vivo. Pharmacological validation using the HRH1-specific antagonist terfenadine confirmed the anti-tumor effects of HRH1 targeting. Based on these findings, we developed an HRH1-targeting mAb that demonstrated potent anti-tumor activity in GBM xenograft models. Mechanistic investigations revealed that the therapeutic effect was mediated through protein kinase C (PKC)-dependent regulation of the RAF/MEK/ERK signaling pathway. In conclusion, we provided a new target, HRH1, for treating GBM and constructed an effective therapeutic mAb.

DOI: https://doi.org/10.1038/s41388-025-03613-8
Immunity. 2025 Oct 21. pii: S1074-7613(25)00429-7. [Epub ahead of print]

Spatial immune profiling defines a subset of human gliomas with functional tertiary lymphoid structures.

Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller.

  Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically "cold" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.

Keywords:  B cells; adaptive immune receptor repertoire; adult-type diffuse glioma; blood-brain barrier; glioblastoma; immune aggregate; spatial molecular profiling; spatial transcriptomics; tertiary lymphoid structures; tumor immunology

DOI:  https://doi.org/10.1016/j.immuni.2025.09.018
Nat Biomed Eng. 2025 Oct 22.

Targeting immunosuppressive myeloid cells via implant-mediated slow release of small molecules to prevent glioblastoma recurrence.

Yannik Kaiser, Christopher S Garris, Eliana Marinari, Hyung Shik Kim, Juhyun Oh, Martin Pedard, Elias A Halabi, Moonhyun Choi, Sepideh Parvanian, Rainer Kohler, Denis Migliorini, Ralph Weissleder.

Glioblastoma is a highly aggressive brain tumour with a high risk of recurrence after surgery, even when combined with chemotherapy and radiotherapy. A major barrier to lasting treatment is the tumour's immunosuppressive environment, which is largely dominated by myeloid cells. Here we describe the development of a biodegradable implant to sustainably release immune-modulator small molecules to reprogram tumour-infiltrating myeloid cells toward a pro-inflammatory, antitumour phenotype in the surgical cavity after tumour removal. In immunocompetent mouse models, this therapy induces interleukin-12 expression in myeloid cells without systemic cytokine elevation, and increases the infiltration of CD8+ and CD4+ T cells. Over 50% of mice treated (in combination with radiotherapy and chemotherapy) remain tumour-free during the experimental course (80 days). We further treated human glioblastoma explants ex vivo with the therapy and observed increased interleukin-12 expression in tumour-infiltrating myeloid cells, supporting the translational potential of this strategy. This implantable system offers a promising approach to prevent glioblastoma recurrence by activating innate immunity and sustaining immune surveillance post-surgery.

DOI: https://doi.org/10.1038/s41551-025-01533-2