bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–02–22
eight papers selected by
Oltea Sampetrean, Keio University
  1. STING-induced blood-brain barrier opening combined with radiotherapy potentiates antitumor response in a high-grade glioma model.
  2. Imaging Biomarkers for Detecting IDH-mutations and Monitoring Response to Novel Targeted Therapies: Current Insights and Future Perspectives.
  3. Tumor-associated astrocytes augment cholesterol synthesis to support glioblastoma growth through alternatively spliced Quaking (QKI) isoforms.
  4. The cellular and mutational origins of IDH mutant glioma.
  5. Protocol to establish glioma stem cell spheroids and an enriched cancer-associated fibroblast population from a single patient tumor specimen.
  6. Astrocytes in the glioblastoma tumor microenvironment.
  7. Long-acting interleukin-7 improves the efficacy of oncolytic viral therapy in glioblastoma.
  8. NF-κB and STAT3 signaling uniquely stratify survival in female glioblastoma patients.
  1. J Clin Invest. 2026 Feb 16. pii: e198843. [Epub ahead of print]136(4):
    STING-induced blood-brain barrier opening combined with radiotherapy potentiates antitumor response in a high-grade glioma model.
    Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen McCortney, Karl J Habashy, Peng Zhang, Craig M Horbinski, Lara Leoni, Ryan J Avery, Rimas V Lukas, Timothy L Sita, David R Raleigh, Sean Sachdev, Roger Stupp, Maciej S Lesniak, David M Ashley, Daniele Procissi, Michael A Curran, Irina Balyasnikova, Amy B Heimberger.
      Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect was maintained in Sting-/- CT-2A cells, highlighting the direct role of the immune system in mediating the survival benefit. Single-cell RNA-Seq identified increased nitric oxide synthase 2 (Nos2) in inflammatory tumor-associated macrophages; however, the therapeutic effect was maintained in Nos2-/- mice. Additionally, 8803 reprogrammed the blood-brain barrier (BBB) by altering the Pecam and Cd147 pathways in endothelial cells; intracranial injection of 8803 induced bihemispheric BBB opening for up to 24 hours. Sting activation was visualized longitudinally using 3'-deoxy-3'-[18F]-fluorothymidine ([18F]-FLT) PET, which peaked 72-96 hours after 8803 administration. In summary, 8803 combined with RT triggers distinctive antiglioma immune reactivity, facilitates BBB opening, and warrants consideration for up-front clinical trials in glioblastoma, where treatment effects can be monitored using [18F]-FLT PET imaging.
    Keywords:  Brain cancer; Cancer immunotherapy; Immunology; Oncology; Therapeutics; Vascular biology
    DOI:  https://doi.org/10.1172/JCI198843
  2. Neuro Oncol. 2026 Feb 16. pii: noag028. [Epub ahead of print]
    Imaging Biomarkers for Detecting IDH-mutations and Monitoring Response to Novel Targeted Therapies: Current Insights and Future Perspectives.
    Archith Rajan, Felipe Rosero Castro, Laiz Laura de Godoy, Mauro Hanaoka, Sevçan Turk, Lisa Desiderio, Roger Stupp, Suyash Mohan, Sanjeev Chawla.
      Isocitrate dehydrogenase (IDH) mutant gliomas represent a unique molecular subset of gliomas with distinct metabolic and microstructural characteristics. The recent approval of targeted IDH inhibitors marks a significant advancement in glioma therapy, thereby necessitating robust, quantitative methods for non-invasive assessment of treatment response. This review provides an overview of advanced multiparametric imaging techniques- including proton MR spectroscopy (1H-MRS), diffusion and perfusion MRI, amide proton transfer imaging (APT), and amino acid PET imaging-and their role in detecting IDH-mutations and monitoring therapeutic response to IDH inhibitors. Special emphasis is placed on metabolic imaging of the oncometabolite D-2-hydroxyglutarate (2-HG), a hallmark signature of IDH-mutant gliomas, and how its quantification serves as a surrogate biomarker for diagnosis and treatment monitoring. We also highlight the potential of advanced diffusion MRI based models, which capture microstructural alterations beyond conventional ADC metrics. Some limitations of these techniques in clinical translation are also considered, along with future directions to integrate them into prospective clinical trials.
    Keywords:   IDH-mutant gliomas; D-2-hydroxyglutarate; Multiparametric imaging; Novel IDH inhibitors; Therapeutic response
    DOI:  https://doi.org/10.1093/neuonc/noag028
  3. Neuro Oncol. 2026 Feb 17. pii: noag030. [Epub ahead of print]
    Tumor-associated astrocytes augment cholesterol synthesis to support glioblastoma growth through alternatively spliced Quaking (QKI) isoforms.
    Runxin Wu, Xiaozhou Yu, Xiao Song, Qiu He, Maya Walker, Derek Sisbarro, Craig Horbinski, Deanna Tiek, Bo Hu, Nu Zhang, Shi-Yuan Cheng.
       BACKGROUND: Glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options. Tumor-associated astrocytes (TAAs) are crucial components of the GBM microenvironment, yet the contribution of alternative splicing (AS) in TAAs to tumor progression remains unclear.
    METHODS: Transcriptomic and molecular analyses of GBM-associated astrocytes revealed a GBM-induced isoform switch in the RNA-binding protein Quaking (QKI) from the QKI-6 isoform to QKI-5 isoform. The biological role of QKI-5 was examined through gain- and loss-of-function approaches in human astrocytes and co-culture systems with patient-derived glioma stem-like cells (GSCs). In vitro proliferation and sphere-formation assays, along with in vivo orthotopic xenograft models, were used to evaluate tumor growth. Immunoprecipitation and AlphaFold3 structural prediction were performed to investigate the mechanistic interaction between QKI-5 and sterol regulatory element-binding protein 2 (SREBP2).
    RESULTS: GBM-induced QKI-5 interacts with SREBP2 to transcriptionally activate cholesterol metabolic enzymes, enhancing astrocyte-derived cholesterol production and promoting GBM growth. Knockdown of QKI-5 or inhibitors for SREBP2-driven signaling suppressed astrocyte-mediated tumor-supportive effects in vitro and in vivo.
    CONCLUSION: QKI-5 drives astrocytic metabolic reprogramming via the QKI-5-SREBP2 axis, fostering a cholesterol-rich tumor microenvironment that supports GBM progression. Targeting this pathway offers a potential therapeutic strategy.
    Keywords:  Alternative splicing; Cholesterol metabolism; Glioblastoma; Quaking (QKI); Tumor-associated astrocyte
    DOI:  https://doi.org/10.1093/neuonc/noag030
  4. Neuro Oncol. 2026 Feb 19. pii: noag034. [Epub ahead of print]
    The cellular and mutational origins of IDH mutant glioma.
    Benjamin J Lerman, Olivia M Doyle, Joseph F Costello.
      
    DOI:  https://doi.org/10.1093/neuonc/noag034
  5. STAR Protoc. 2026 Feb 19. pii: S2666-1667(26)00012-2. [Epub ahead of print]7(1): 104359
    Protocol to establish glioma stem cell spheroids and an enriched cancer-associated fibroblast population from a single patient tumor specimen.
    Caroline Delmas, Elisabeth Cohen-Jonathan-Moyal, Catherine Seva.
      Glioblastoma is an aggressive, therapy-resistant brain tumor in which the role of cancer-associated fibroblasts (CAFs) remains poorly defined. We present a protocol to simultaneously establish glioblastoma stem cell (GSCs) spheroids and CAFs from a single patient specimen. We describe steps to dissociate tumor tissue, generate a single-cell suspension, and establish GSCs spheroids and CAFs cultures. This protocol details CAFs enrichment, passaging, phenotypic characterization, and cryopreservation. For complete details on the use and execution of this protocol, please refer to Delmas et al.1.
    Keywords:  Cancer; Cell culture; Cell isolation; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2026.104359
  6. Neuro Oncol. 2025 Nov 01. 27(11): 2749-2750
    Astrocytes in the glioblastoma tumor microenvironment.
    Camilo Faust Akl, Brian M Andersen, Francisco J Quintana.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf191
  7. Nat Commun. 2026 Feb 17.
    Long-acting interleukin-7 improves the efficacy of oncolytic viral therapy in glioblastoma.
    Yuping Derek Li, David A Giles, Yi Huang, Ashwani Kesarwani, Tong Hu, Logan Page, Amanda de Andrade Costa, Jingqin Luo, Alexandra Wolfarth, Donghoon Choi, Mai T Dang, Albert H Kim, John F DiPersio, David T Curiel, Michael S Diamond, Milan G Chheda.
      Despite advances in immunotherapy, the prognosis for patients with glioblastoma (GBM) remains poor. The efficacy of GBM-targeted immunotherapies is limited by the paucity of functional T cells in the tumor microenvironment, a consequence of the local and systemic immunosuppression prevalent in patients with GBM. To overcome these challenges, here we develop a treatment strategy we term "expand and pull," which uses systemic administration of rhIL-7-hyFc, a long-acting recombinant human interleukin-7, to increase peripheral T cell abundance ("expand"), followed by intratumoral oncolytic virus treatment to recruit these cells to the tumor microenvironment ("pull"). We show that rhIL-7-hyFc improves the efficacy of multiple oncolytic viral therapies in syngeneic immuno-resistant mouse models of glioma. Combining rhIL-7-hyFc and Zika virus (ZIKV) increases systemic and intratumoral T cell abundance, improves cytotoxic T cell function, and delays expression of inhibitory checkpoint receptors, resulting in long-term tumor-free survival. We observe similar survival efficacy in experiments using a safer, genetically modified Δ10 3'-UTR ZIKV, as well as the clinically tested oncolytic adenovirus, Delta24-RGD. Collectively, our findings demonstrate that augmentation of both the systemic and local immune responses improves the utility of GBM-targeted immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-026-69606-7
  8. iScience. 2026 Feb 20. 29(2): 114761
    NF-κB and STAT3 signaling uniquely stratify survival in female glioblastoma patients.
    Jason P Wong, Lorida Llaci, Lloyd Tripp, Myung Sik Jeon, Lihua Yang, Nicholas Reinhold, Nicole M Warrington, Jingqin Luo, Robi D Mitra, Joshua B Rubin.
      The mechanisms underlying sex differences in glioblastoma (GBM) incidence, treatment response, and survival are not well understood. Increased activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling is associated with shorter survival in GBM. We looked at the expression of NF-κB- or STAT3-related genes in GBM for evidence of a sex skew in activity. Survival analysis of male and female GBM patients revealed that NF-κB- or STAT3-related gene expression was correlated with shorter survival only in female patients. We further explored mechanisms of this sex effect in an established murine model of sex differences in GBM. Concordant with human data, female murine GBM cells expressed stronger signatures of NF-κB and STAT3 genes and exhibited stronger responses to pathway stimulation and inhibition than their male counterparts. This study illustrates the advantage of sex-stratified data analysis in the development of sex-informed treatments for greater precision in cancer treatments.
    Keywords:  cancer; health disparity
    DOI:  https://doi.org/10.1016/j.isci.2026.114761
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