bims-malgli 2025-03-30 papers

Issue of 2025–03–30
six papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2025 Mar 25. pii: noaf086. [Epub ahead of print]

Targeting PDGFRA-SHP2 Signaling Enhances Radiotherapy in IDH1-Mutant Glioma.

Xiaozhou Yu, Xiao Song, Deanna Tiek, Runxin Wu, Maya Walker, Craig Horbinski, Bo Hu, Shi-Yuan Cheng.

BACKGROUND: Isocitrate dehydrogenase mutant (IDH-mut) gliomas represent a distinct subtype of glioma, characterized by a relatively better prognosis compared to IDH wildtype (wt) glioblastoma (GBM). Despite this advantage, these tumors remain incurable due to the limited availability of effective treatments. Targeting SHP2, a non-receptor protein tyrosine phosphatase, is a promising therapeutic strategy for several types of human cancers. In this study, we aim to determine the efficacy of SHP inhibition in IDH-mut gliomas.
METHODS: Bioinformatic and biological analyses revealed increased expression and activation of the PDGFRA-SHP2-ERK pathway in clinical IDH-mut gliomas and patient-derived IDH-mut glioma stem-like cells (GSCs). The effects of SHP2 inhibition, alone or with radiation therapy (RT), were assessed through assays including cell growth, sphere formation, cell differentiation markers, flow cytometry, immunoblotting, immunohistochemistry, and orthotopic brain tumor xenografts.
RESULTS: PDGFRA expression was elevated in IDH-mut gliomas and GSCs, activating the SHP2-ERK pathway. SHP099, a SHP2 inhibitor, reduced GSC tumorigenicity in vitro and in vivo by disrupting SHP2-ERK signaling and promoting differentiation. SHP099 also enhanced cytotoxicity of RT, the standard treatment for IDH-mut glioma, in IDH-mut GSCs and orthotopic glioma models. Mechanistically, the PDGFRA-SHP2-ERK axis is activated in IDH-mut gliomas and RT further activates this pathway. Targeting SHP2 suppressed ERK signaling thereby enhancing the therapeutic effect of RT.
CONCLUSION: Combining SHP2 inhibition with RT is a promising therapeutic avenue for IDH-mut glioma by suppressing the activated SHP2-ERK axis.

Keywords: IDH-mutant gliomas; PDGFRA; SHP2; differentiation; radiation therapy

DOI: https://doi.org/10.1093/neuonc/noaf086

J Clin Invest. 2025 Mar 25. pii: e186034. [Epub ahead of print]

Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models.

Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D Lathia, Peiwen Chen.

Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3b-STAT3 pathway. Moreover, TAM-derived LGMN activated the integrin aV-AKT-P65 signaling to drive GBM cell proliferation and survival. Targeting LGMN-directed macrophage (inhibiting GSK3b and STAT3) and GBM cell (inhibiting integrin aV) mechanisms resulted in an anti-tumor effect in immunocompetent GBM mouse models that was further enhanced when combined with anti-PD1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN in promoting GBM progression and immunosuppression, providing effective therapeutic targets for improving immunotherapy in GBM.

Keywords: Brain cancer; Immunology; Immunotherapy; Macrophages; Oncology

DOI: https://doi.org/10.1172/JCI186034

Cancer Sci. 2025 Mar 23.

Opportunities to Modulate Tumor Ecosystem Toward Successful Glioblastoma Immunotherapy.

Mariko Takahashi, Darina Mukhamejanova, Himani Jasewicz, Nandini Acharya, James J Moon, Toshiro Hara.

Over the past decade, the failure of multiple clinical trials has confirmed the need for a systematic and comprehensive understanding of glioblastoma (GBM). Current immunotherapies aiming to harness the immune system to achieve anti-tumor effects remain largely ineffective, highlighting the complexities of the GBM microenvironment. However, our recent understanding of immune niches within the central nervous system provides both opportunities and challenges in translating these insights into successful immunotherapy implementation. We discuss these strategies, including targeting multiple antigens within the heterogeneous GBM microenvironment, identifying new druggable targets to abrogate immunosuppression, and understanding niche-specific immune cell functionality to modulate tumor-immune-stroma interactions.

DOI: https://doi.org/10.1111/cas.70052

Acta Neuropathol Commun. 2025 Mar 21. 13(1): 64

Curative timed NK cell-based immunochemotherapy aborts brain tumour recurrence driven by mesenchymal glioma stem cells.

Brian Meehan, Lata Adnani, Xianbing Zhu, Nadim Tawil, Delphine Garnier, Ichiro Nakano, Sidong Huang, Janusz Rak.

High grade gliomas (HGG) are incurable brain cancers, where inevitable disease recurrence is driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) chemotherapy, amidst weak immune and natural killer (NK) cell surveillance. The present study was designed to understand how to enhance the contribution of innate immunity to post TMZ disease control. Strikingly, molecular subtypes of HGG impacted the repertoire of NK cell sensitivity markers across human HGG transcriptomes, and in a panel of GSCs with either proneural (PN-GSC) or mesenchymal (MES-GSC) phenotypes. Indeed, only MES-GSCs (but not PN-GSCs) were enriched for NK cell ligands and sensitive to NK-mediated cytotoxicity in vitro. While NK cells alone had no effect on HGG progression in vivo, the post-chemotherapy (TMZ) recurrence of MES-GSC-driven xenografts was aborted by timed intracranial injection of live or irradiated NK (NK92MI) cells, resulting in long term survival of animals. This curative effect declined when NK cell administration was delayed relative to TMZ exposure pointing to limits of the immune control over resurging residual tumour stem cell populations that survived chemotherapy. Overall, these results suggest that chemotherapy-dependent tumour depopulation may create a unique window of opportunity for NK-mediated intervention with curative effects restricted to a subset of HGGs driven by mesenchymal brain tumour initiating cells.

Keywords: Glioblastoma; High grade glioma; Intracranial immunotherapy; Intracranial xenografts; Mesenchymal glioma stem cells; Molecular subtypes of glioma; NK cells; Proneural glioma stem cells; Relapse; Temozolomide

DOI: https://doi.org/10.1186/s40478-025-01984-3

Neuro Oncol. 2025 Mar 22. pii: noaf079. [Epub ahead of print]

A multi-institutional phase 1 clinical trial exploring upfront multimodal standard of care and combined immunotherapies for newly diagnosed glioblastoma.

Patrick Y Wen, Andrea Manzanera, Caroline Duault, Edgar Gonzalez-Kozlova, Lenika Lopez, Stuart A Grossman, Xiaobu Ye, Joy Fisher, Ian Lee, Tobias Walbert, James Snyder, Steven Brem, Arati Desai, Stephen J Bagley, Chandana Kakani, Roy Strowd, Stephen Tatter, Adrian Laxton, Glenn Lesser, Nduka Amankulor, Frank Lieberman, Jan Drappatz, Megan Mantica, Dan Triggs, Cara Haymaker, Ignacio I Wistuba, Gheath Al-Atrash, Julia Mendoza Perez, Andrew Futreal, Latasha D Little, M D Habibul Islam, Dzifa Duose, Peixin Jiang, Alexandre Reuben, Sean E Lawler, Mina Pichavant, Andrew Gentles, Sean Bendall, Alex Kong, Christine Camacho, Diane Del Valle, Seunghee Kim-Schulze, Sacha Gnjatic, Elad Sharon, M Oskar Nowicki, Pierpaolo Peruzzi, Doug Lane, Estuardo Aguilar-Cordova, Laura K Aguilar, Garrett Nichols, Jessica Dwyer, Paul Peter Tak, Holden Maecker, Francesca Barone, E Antonio Chiocca.

BACKGROUND: For newly diagnosed glioblastoma (GBM), combination of surgical upfront immunotherapy with aglatimagene besadenovec (CAN-2409), followed by chemoradiation and then adjuvant nivolumab has not been tested. The aim of this study was to test the safety of this regimen and determine metrics of immune activation that may correlate with clinical outcomes.
METHODS: 41 patients with suspected newly diagnosed GBM by imaging were enrolled in this multi-institutional, open label, phase 1b clinical trial before surgical resection. Frozen section confirmation of high-grade glioma was required for administration of aglatimagene besadenovec. This was then followed with chemoradiation and adjuvant nivolumab. Tumor and blood were assayed for genetic and immune markers before and during treatment.
RESULTS: The regimen was well tolerated and generated measurable immune activation. Factors linked to survival were identified, such as baseline mutated gene pairs (e.g. MED15/ HRC), tumor immune cell composition, and changes in systemic cytokine, immune cells, and T cell diversity. The most significant serial systemic immune changes were observed in a long-term survivor subset of patients with gross total resection (GTR)/ methylated methylguanine methyltransferase (MGMT) promoter tumors. Median overall survival (mOS) in these patients was 30.6 months, while it was less for patients with unmethylated or subtotal resections.
CONCLUSIONS: These findings suggest the opportunity for patient stratification and the potential for more durable antitumor immune responses in future clinical trials of this multimodal standard of care and combined immunotherapy regimen. ClinicalTrials.gov identifier: NCT03576612.

Keywords: Clinical trial; brain tumor; gene therapy; glioma; immunotherapy

DOI: https://doi.org/10.1093/neuonc/noaf079

Nat Commun. 2025 Mar 26. 16(1): 2974

Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression.

Glioblastoma (GBM) is the most lethal primary brain tumor with intra-tumoral hierarchy of glioblastoma stem cells (GSCs). The heterogeneity of GSCs within GBM inevitably leads to treatment resistance and tumor recurrence. Molecular mechanisms of different cellular state GSCs remain unclear. Here, we find that classical (CL) and mesenchymal (MES) GSCs are enriched in reactive immune region and high CL-MES signature informs poor prognosis in GBM. Through integrated analyses of GSCs RNA sequencing and single-cell RNA sequencing datasets, we identify specific GSCs targets, including MEOX2 for the CL GSCs and SRGN for the MES GSCs. MEOX2-NOTCH and SRGN-NFκB axes play important roles in promoting proliferation and maintaining stemness and subtype signatures of CL and MES GSCs, respectively. In the tumor microenvironment, MEOX2 and SRGN mediate the resistance of CL and MES GSCs to macrophage phagocytosis. Using genetic and pharmacologic approaches, we identify FDA-approved drugs targeting MEOX2 and SRGN. Combined CL and MES GSCs targeting demonstrates enhanced efficacy, both in vitro and in vivo. Our results highlighted a therapeutic strategy for the elimination of heterogeneous GSCs populations through combinatorial targeting of MEOX2 and SRGN in GSCs.

DOI: https://doi.org/10.1038/s41467-025-58366-5