bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–04–13
nine papers selected by
Oltea Sampetrean, Keio University
  1. Epigenetic reprogramming of glioblastoma to overcome chemotherapy resistance.
  2. Multimodal glioma immunotherapy combining TLR9-targeted STAT3 antisense oligodeoxynucleotides with PD1 immune checkpoint blockade.
  3. High-Throughput Screening on Primary Tumor-Associated Microglia and Macrophages Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Partners for Immunotherapy in Glioblastoma.
  4. Plasma-to-tumour tissue integrated proteomics using nano-omics for biomarker discovery in glioblastoma.
  5. The epigenetic mechanisms involved in the treatment resistance of glioblastoma.
  6. Epitranscriptomic analysis reveals clinical and molecular signatures in glioblastoma.
  7. Aurora Kinase A and B inhibition abrogates 'Neosis', a non-mitotic cell division of GBM residual cells and prevents GBM recurrence.
  8. H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition.
  9. Do we need B7-H3 immunohistochemistry for the inclusion of children with high-grade central nervous system tumors in clinical trials targeting B7-H3?
  1. Nat Rev Neurol. 2025 Apr 04.
    Epigenetic reprogramming of glioblastoma to overcome chemotherapy resistance.
    Heather Wood.
      
    DOI:  https://doi.org/10.1038/s41582-025-01083-w
  2. Neuro Oncol. 2025 Apr 11. pii: noaf099. [Epub ahead of print]
    Multimodal glioma immunotherapy combining TLR9-targeted STAT3 antisense oligodeoxynucleotides with PD1 immune checkpoint blockade.
    Chia-Yang Hung, Elaine Y Kang, Karol Jacek, Chunsong Yu, Xiaowei Zhang, Yicheng Zhu, Maryam Aftabizadeh, Robyn A Wong, Benham Badie, Piotr Swiderski, Bożena Kaminska, Darya Alizadeh, Amy B Heimberger, Christine Brown, Marcin Kortylewski.
       BACKGROUND: Therapeutic resistance in glioblastoma (GBM) is multifactorial and results from genetic heterogeneity, the immunoprivileged localization and the potently tolerogenic microenvironment. Signal transducer and activator of transcription 3 (STAT3) plays a key role in both glioma cell survival and immune evasion reinforcing GBM resistance.
    METHODS: Here, we describe a new cell-selective and double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO) for targeting human/mouse glioma cells and GAMs but not T-cells. The oligonucleotide safety and efficacy against orthotopic GBM was assessed in immunocompetent or immunodeficient mice.
    RESULTS: CpG-STAT3dsASO injected intracranially/intratumorally was well-tolerated and reduced progression of human U251 GBM xenotransplants and mouse GL261 or neural cell-derived QPP8 gliomas. Unlike the single-stranded oligonucleotide, local CpG-STAT3dsASO administration did not trigger type-I IFN-dependent neurotoxicities in immunocompetent mice within the therapeutic dose range. CpG-STAT3dsASO activated intratumoral GAMs, such as dendritic cells, macrophages and microglia, thereby expanding CD4+ Th1 cells while reducing TREG numbers. CpG-STAT3dsASO monotherapy did not have curative effects as it led to recruitment of only limited numbers of mostly exhausted effector CD8+ T-cells. However, when combined with systemic PD1 inhibition, CpG-STAT3dsASO/anti-PD1 treatments caused regression of GL261 as well as immunotherapy-resistant QPP8 gliomas and resulted in long-term survival of the majority of mice. The combination treatment boosted CD8+ effector T-cell activity, while promoting their intratumoral interaction with activated CD4+ Th1 cells and activated macrophages as indicated by spatial transcriptomics.
    CONCLUSIONS: Our results suggest rationale for the GBM immunotherapy using CpG-STAT3dsASO to disrupt GAMs-dependent immune evasion, thereby restoring sensitivity to PD1-blockade and facilitating T-cell-mediated antitumor immune responses.
    Keywords:  Glioblastoma; PD1; STAT3; TLR9; antisense oligonucleotide
    DOI:  https://doi.org/10.1093/neuonc/noaf099
  3. bioRxiv. 2025 Mar 27. pii: 2025.03.24.645104. [Epub ahead of print]
    High-Throughput Screening on Primary Tumor-Associated Microglia and Macrophages Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Partners for Immunotherapy in Glioblastoma.
    Mona Khalaj, Madison L Gutierrez, Parisa Nejad, Tal Raveh, Faranak Fattahi, Irving L Weissman.
      Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted the first large-scale chemical screen on primary TAMs from patients with GBM, identifying histone deacetylase (HDAC) inhibitors as potent inducers of phagocytosis. These compounds demonstrated phagocytosis-inducing effects across multiple GBM patient samples, with further amplification when combined with CD47 blockade. In a xenograft GBM model, HDAC inhibitors enhanced phagocytosis and suppressed tumor growth, with even greater efficacy in combination with CD47 antibodies. Our findings highlight HDAC inhibitors as promising agents to reprogram TAMs and synergize with immune checkpoint therapies, offering a novel strategy to bolster anti-tumor immunity in GBM.
    DOI:  https://doi.org/10.1101/2025.03.24.645104
  4. Nat Commun. 2025 Apr 10. 16(1): 3412
    Plasma-to-tumour tissue integrated proteomics using nano-omics for biomarker discovery in glioblastoma.
    Xinming Liu, Hanan Abmanhal-Masarweh, Olivia Iwanowytsch, Emmanuel Okwelogu, Kiana Arashvand, Konstantina Karabatsou, Pietro Ivo D'Urso, Federico Roncaroli, Kostas Kostarelos, Thomas Kisby, Marilena Hadjidemetriou.
      Glioblastoma (GB) is the most lethal brain cancer, with patient survival rates remaining largely unchanged over the past two decades. Here, we introduce the Nano-omics integrative workflow that links systemic (plasma) and localised (tumour tissue) protein changes associated with GB progression. Mass spectrometry analysis of the nanoparticle biomolecule corona in GL261-bearing mice at different stages of GB revealed plasma protein alterations, even at low tumour burden, with over 30% overlap between GB-specific plasma and tumour tissue proteomes. Analysis of matched plasma and surgically resected tumour samples from high-grade glioma patients demonstrates the clinical applicability of the Nano-omics pipeline. Cross-species correlation identified 48 potential GB biomarker candidates involved in actin cytoskeleton organisation, focal adhesion, platelet activation, leukocyte migration, amino acid biosynthesis, carbon metabolism, and phagosome pathways. The Nano-omics approach holds promise for the discovery of early detection and disease monitoring biomarkers of central nervous system conditions, paving the way for subsequent clinical validation.
    DOI:  https://doi.org/10.1038/s41467-025-58252-0
  5. Cancer Drug Resist. 2025 ;8 12
    The epigenetic mechanisms involved in the treatment resistance of glioblastoma.
    Aanya Shahani, Hasan Slika, Ahmad Elbeltagy, Alexandra Lee, Christopher Peters, Toriyn Dotson, Divyaansh Raj, Betty Tyler.
      Glioblastoma (GBM) is an aggressive malignant brain tumor with almost inevitable recurrence despite multimodal management with surgical resection and radio-chemotherapy. While several genetic, proteomic, cellular, and anatomic factors interplay to drive recurrence and promote treatment resistance, the epigenetic component remains among the most versatile and heterogeneous of these factors. Herein, the epigenetic landscape of GBM refers to a myriad of modifications and processes that can alter gene expression without altering the genetic code of cancer cells. These processes encompass DNA methylation, histone modification, chromatin remodeling, and non-coding RNA molecules, all of which have been found to be implicated in augmenting the tumor's aggressive behavior and driving its resistance to therapeutics. This review aims to delve into the underlying interactions that mediate this role for each of these epigenetic components. Further, it discusses the two-way relationship between epigenetic modifications and tumor heterogeneity and plasticity, which are crucial to effectively treat GBM. Finally, we build on the previous characterization of epigenetic modifications and interactions to explore specific targets that have been investigated for the development of promising therapeutic agents.
    Keywords:  DNA methylation; epigenetics; glioblastoma; histone modification; miRNA; treatment resistance; tumoral heterogeneity
    DOI:  https://doi.org/10.20517/cdr.2024.157
  6. Acta Neuropathol Commun. 2025 Apr 11. 13(1): 74
    Epitranscriptomic analysis reveals clinical and molecular signatures in glioblastoma.
    Glaucia Maria de Mendonça Fernandes, Wesley Wang, Saman Seyed Ahmadian, Daniel Jones, Jing Peng, Pierre Giglio, Monica Venere, José Javier Otero.
      This study characterizes the glioblastoma (GB) epitranscriptomic landscape in patient who evolve to progressive disease (PD) or pseudo-progressive disease (psPD). Novel differences in N6-Methyladenosine (m6A) RNA methylation patterns between these groups are identified in the first biopsy. Retrospective data of patients that were eventually deemed to have progressive disease or pseudoprogressive disease was captured from the electronic health record, and RNA from the first resection specimen was utilized to evaluate N6-methyladenosine (m6A) biomarkers from FFPE samples. Molecular analysis of m6A methylation modified RNA employed ACA-based RNase MazF digestion. After Quantitative Normalization with ComBat to mitigate batch effects, we identifed differentially methylated transcripts and gene expression analyses, co-expression networks analyses with WGCNA, and subsequently performed gene set GO and KEGG enrichment analyses. Enrichments for metabolic biological processes and pathways were identified in our differential methylated transcripts and select module eigengene networks highlighted key co-expressed genes intricately tied to distinct phenotypes/traits in patients that would ultimately be deemed PD or psPD. Our study identified key genes and pathways modified by m6A RNA methylation associated with cell metabolism alterations, highlighting the importance of understanding m6A mechanisms leading to the oncometabolite accumulation governing PD versus psPD patients. Furthermore, these data indicate that epitranscriptomal differences between PD versus psPD are detected early in the disease course.
    Keywords:  Epitranscriptome; Glioblastoma; Novel enhancement; Progression disease; Pseudo-progression
    DOI:  https://doi.org/10.1186/s40478-025-01966-5
  7. Oncogene. 2025 Apr 07.
    Aurora Kinase A and B inhibition abrogates 'Neosis', a non-mitotic cell division of GBM residual cells and prevents GBM recurrence.
    Tejashree Mahaddalkar, Archisman Banerjee, Madhura Ketkar, Rahul Thorat, Nilesh Gardi, Shilpee Dutt.
      Glioblastoma (GBM) has a dismal median survival of 15 months owing to therapy resistance and inevitable recurrence. Using our cellular models of GBM radiation resistance, we had shown that GBM recurrence is due to survival and proliferation of residual disease cells enriched in multinucleated giant cells (MNGCs). However, MNGC division mechanism remained elusive. Here, using live-cell imaging we found daughter cells emerge from MNGCs by cytoplasmic pinching. Lack of DNA condensation, absence of spindle poles and acto-myosin contractile ring in dividing-MNGCs confirmed non-mitotic division of MNGCs. Furthermore, MNGCs harboured DNA damage, senescence phenotype, repeated atypical division after radiation exposure, characteristics of unconventional division called 'Neosis'. Molecularly, WGCNA co-expression network analysis of RNA-Sequencing from parent, non-dividing MNGCs and dividing-MNGCs identified significantly high expression of aurora kinases (AurA and AurB) specifically in dividing-MNGCs. Pharmacological and genetic inhibition of aurora kinases abrogated MNGC neosis, preventing GBM recurrence in vitro and in vivo in an orthotopic GBM mouse model. Together, this study demonstrates that MNGCs divide by neosis, an atypical division mediated by AurA and AurB and identify aurora kinases as a potential molecular target to inhibit neosis and prevent GBM recurrence.
    DOI:  https://doi.org/10.1038/s41388-025-03372-6
  8. Neuro Oncol. 2025 Apr 10. pii: noaf097. [Epub ahead of print]
    H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition.
    Yupei Guo, Zian Li, Leslie A Parsels, Zhuwen Wang, Joshua D Parsels, Anushka Dalvi, Stephanie The, Nan Hu, Victoria M Valvo, Robert Doherty, Erik Peterson, Xinjun Wang, Sujatha Venkataraman, Sameer Agnihotri, Sriram Venneti, Daniel R Wahl, Michael D Green, Theodore S Lawrence, Carl Koschmann, Meredith A Morgan, Qiang Zhang.
       BACKGROUND: Radiotherapy (RT) is the primary treatment for diffuse midline glioma (DMG), a lethal pediatric malignancy defined by histone H3 lysine 27-to-methionine (H3K27M) mutation. Based on the loss of H3K27 trimethylation producing broad epigenomic alterations, we hypothesized that H3K27M causes a functional double-strand break (DSB) repair defect that could be leveraged therapeutically with PARP inhibitor and RT for selective radiosensitization and antitumor immune response.
    METHODS: H3K27M isogenic DMG cells and orthotopic brainstem DMG tumors in immune deficient and syngeneic, immune competent mice were used to evaluate the efficacy and mechanisms of PARP1/2 inhibition by olaparib or PARP1-selective inhibition by AZD9574 with concurrent RT.
    RESULTS: H3K27M mutation caused a homologous recombination repair (HRR) defect characterized by impaired RT-induced K63-linked polyubiquitination of histone H1 and inhibition of HRR protein recruitment. H3K27M DMG cells were selectively radiosensitized by olaparib in comparison to isogenic controls, and this effect translated to efficacy in H3K27M orthotopic brainstem tumors. Olaparib and RT induced an innate immune response and induction of NK cell (NKG2D) activating ligands leading to increased NK cell-mediated lysis of DMG cells. In immunocompetent syngeneic orthotopic DMG tumors, either olaparib or AZD9574 in combination with RT enhanced intratumoral NK cell infiltration and activity in association with NK cell-mediated therapeutic responses and favorable activity of AZD9574.
    CONCLUSIONS: The HRR deficiency in H3K27M DMG can be therapeutically leveraged with PARP inhibitors to radiosensitize and induce an NK cell-mediated antitumor immune response selectively in H3K27M DMG, supporting the clinical investigation of PARP1 inhibitors with RT in DMG patients.
    Keywords:  Diffuse midline glioma; H3K27M; NK cell; PARP inhibitor; antitumor immune response
    DOI:  https://doi.org/10.1093/neuonc/noaf097
  9. Neuro Oncol. 2025 Apr 09. pii: noaf095. [Epub ahead of print]
    Do we need B7-H3 immunohistochemistry for the inclusion of children with high-grade central nervous system tumors in clinical trials targeting B7-H3?
    Mariëtte E G Kranendonk, Raoull Hoogendijk, Julie A S Lammers, Jasper van der Lugt, Nelleke Tolboom, Esther van Mastrigt, Ella de Boed, Thijs J M van den Broek, Lennart Kester, Dannis G van Vuurden, Bastiaan B J Tops, Eelco W Hoving, Pieter Wesseling, Sabine L A Plasschaert.
       BACKGROUND: Pediatric high-grade central nervous system (pHG-CNS) tumors are the leading cause of childhood cancer-related deaths, partly due to poor response to standard treatments. B7-H3 is reportedlyexpressed in pHG-CNS tumors, making antigen-targeting therapies, including anti-B7-H3 chimeric antigen receptor T-cell (CAR-T) therapy, promising. However, given substantial inter-tumoral protein expression diversity in CNS tumors, it's unclear which patients might benefit from these treatments. Therefore, we studied B7-H3 expression in a large set of pHG-CNS tumors.
    METHODS: We retrospectively analyzed 136 pHG-CNS tumors (embryonal tumors (n=44), high-grade neuroepithelial tumors (n=4), ependymomas (n=30),high-grade gliomas (HGGs, n=58)) from the Princess Máxima Center for Pediatric Oncology. CD276 mRNA (encoding B7-H3) and immunohistochemical (IHC) protein expression of B7-H3 was measured and correlated to clinical-molecular data.
    RESULTS: Large variability of B7-H3 mRNA and protein expression was observed both between and within tumor types. Many tumors expressed B7-H3, but 30% of diffuse midline glioma H3K27-altered and ependymomas posterior fossa type A showed no or minimal expression. This variability was unrelated to patient age, tumor location, epigenetic subclass, or molecular tumor driver. B7-H3 negative cases were high in tumor cells, ruling out low tumor cell percentage as explanation for negative staining.
    CONCLUSIONS: Our study of B7-H3-expression in the largest pHG-CNS tumor set to date revealed significant interpatient variability and numerous negative cases. Our results urge for tumor tissue acquisition at enrollment in B7-H3 targeting therapeutic trials (including CAR-T cells) in order to thoroughly assess the value of IHC B7-H3 expression as biomarker and, ultimately, to allow for more tailored therapy.
    Keywords:  B7-H3; antigen-targeting therapy; diffuse midline glioma; pediatric CNS tumor
    DOI:  https://doi.org/10.1093/neuonc/noaf095
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