bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–03–16
eight papers selected by
Oltea Sampetrean, Keio University
  1. SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma.
  2. Veliparib Plus Temozolomide for MGMT-Methylated Glioblastoma.
  3. GCN5-targeted dual-modal probe across the blood-brain barrier for borders display in invasive glioblastoma.
  4. Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples.
  5. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib.
  6. Germline analysis of an international cohort of pediatric diffuse midline glioma patients.
  7. Convection enhanced delivery of Rhenium (186Re) Obisbemeda (186RNL) in recurrent glioma: a multicenter, single arm, phase 1 clinical trial.
  8. Dual Inhibition of MAPK and TORC1 Signaling Retards Development of Radiation Resistance in Pediatric BRAFV600E Glioma Models.
  1. JCI Insight. 2025 Mar 10. pii: e186344. [Epub ahead of print]10(5):
    SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma.
    Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau V Vo, Timothy Y Huang, Charles Spruck, Richard L Carpenter, Y Alan Wang, Q Richard Lu, Kenneth P Nephew, Jia Shen.
      Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer-mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.
    Keywords:  Cancer; Cell biology; Oncology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.186344
  2. JAMA Oncol. 2025 Mar 13.
    Veliparib Plus Temozolomide for MGMT-Methylated Glioblastoma.
    Liam Wilson, Aline Atallah.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2025.0029
  3. Nat Commun. 2025 Mar 08. 16(1): 2345
    GCN5-targeted dual-modal probe across the blood-brain barrier for borders display in invasive glioblastoma.
    Haiyan Zheng, Lu Zhang, Xinning Bai, Jinchao Zhu, Shanshan Liu, Yao Ke, Qingyuan Lin, Yuan Yuan, Tianhai Ji.
      Glioblastoma (GBM) is a highly invasive malignancy with a poor prognosis, primarily attributable to its diffuse infiltration into adjacent brain tissue, thereby complicating effective surgical resection. Current imaging modalities often struggle to accurately identify tumor boundaries. Here, we identify general control non-repressed protein 5 (GCN5) as a promising molecular target for GBM imaging, as it is expressed in GBM lesions within brain tissue, and its expression levels are significantly correlated with GBM grading. We develop a dual-modal probe with a particle size of 20 nm, capable of efficiently traversing the blood-brain barrier (BBB) to target GCN5 through adsorptive-mediated transcytosis (AMT). The probe employs dendrimers (Den) as carriers, which are loaded with a small molecule inhibitor specifically designed to target GCN5. This probe enhances the preoperative delineation of GBM boundaries using magnetic resonance imaging (MRI) and facilitates intraoperative fluorescence image-guided surgical procedures. Our work introduces a promising tool for boundary delineation, offering new opportunities for the precise resection of GBM.
    DOI:  https://doi.org/10.1038/s41467-025-57598-9
  4. Sci Adv. 2025 Mar 14. 11(11): eadn2830
    Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples.
    Qixuan Wang, Juan Wang, Radhika Mathur, Mark W Youngblood, Qiushi Jin, Ye Hou, Lena Ann Stasiak, Yu Luan, Hengqiang Zhao, Stephanie Hilz, Chibo Hong, Susan M Chang, Janine M Lupo, Joanna J Phillips, Joseph F Costello, Feng Yue.
      Glioblastoma (GBM) is the most prevalent malignant brain tumor with poor prognosis. Although chromatin intratumoral heterogeneity is a characteristic feature of GBM, most current studies are conducted at a single tumor site. To investigate the GBM-specific 3D genome organization and its heterogeneity, we conducted Hi-C experiments in 21 GBM samples from nine patients, along with three normal brain samples. We identified genome subcompartmentalization and chromatin interactions specific to GBM, as well as extensive intertumoral and intratumoral heterogeneity at these levels. We identified copy number variants (CNVs) and structural variations (SVs) and demonstrated how they disrupted 3D genome structures. SVs could not only induce enhancer hijacking but also cause the loss of enhancers to the same gene, both of which contributed to gene dysregulation. Our findings provide insights into the GBM-specific 3D genome organization and the intratumoral heterogeneity of this organization and open avenues for understanding this devastating disease.
    DOI:  https://doi.org/10.1126/sciadv.adn2830
  5. Cancer Cell. 2025 Mar 04. pii: S1535-6108(25)00070-4. [Epub ahead of print]
    Effective targeting of PDGFRA-altered high-grade glioma with avapritinib.
    Lisa Mayr, Sina Neyazi, Kallen Schwark, Maria Trissal, Alexander Beck, Jenna Labelle, Sebastian K Eder, Liesa Weiler-Wichtl, Joana G Marques, Carlos A O de Biagi-Junior, Costanza Lo Cascio, Owen Chapman, Sunita Sridhar, Rishaan Kenkre, Aditi Dutta, Shanqing Wang, Jessica Wang, Olivia Hack, Andrezza Nascimento, Cuong M Nguyen, Sophia Castellani, Jacob S Rozowsky, Andrew Groves, Eshini Panditharatna, Gustavo Alencastro Veiga Cruzeiro, Rebecca D Haase, Kuscha Tabatabai, Sibylle Madlener, Jack Wadden, Tiffany Adam, Seongbae Kong, Madeline Miclea, Tirth Patel, Katharina Bruckner, Daniel Senfter, Anna Lämmerer, Jeffrey Supko, Armin S Guntner, Hana Palova, Jakub Neradil, Natalia Stepien, Daniela Lötsch-Gojo, Walter Berger, Ulrike Leiss, Verena Rosenmayr, Christian Dorfer, Karin Dieckmann, Andreas Peyrl, Amedeo A Azizi, Alicia Baumgartner, Ondrej Slaby, Petra Pokorna, Louise M Clark, Amy Cameron, Quang-De Nguyen, Hiroaki Wakimoto, Frank Dubois, Noah F Greenwald, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Christof Kramm, Annika Bronsema, Simon Bailey, Ana Guerreiro Stucklin, Sabine Mueller, Mary Skrypek, Nina Martinez, Daniel C Bowers, David T W Jones, Chris Jones, Natalie Jäger, Jaroslav Sterba, Leonhard Müllauer, Christine Haberler, Chandan Kumar-Sinha, Arul Chinnaiyan, Rajen Mody, Lukas Chavez, Julia Furtner, Carl Koschmann, Johannes Gojo, Mariella G Filbin.
      PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.
    Keywords:  PDGFRA alteration; PDGFRA amplification; PDGFRA inhibitor; PDGFRA mutation; avapritinib; brain penetrance; diffuse midline glioma; glioblastoma; high-grade glioma; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.018
  6. Neuro Oncol. 2025 Mar 12. pii: noaf061. [Epub ahead of print]
    Germline analysis of an international cohort of pediatric diffuse midline glioma patients.
    Marion K Mateos, Pamela Ajuyah, Noemi Fuentes-Bolanos, Sam El-Kamand, Paulette Barahona, Ann-Kristin Altekoester, Chelsea Mayoh, Holly Holliday, Jie Liu, Louise Cui, Elke Pfaff, Alan Mackay, Adam C Resnick, Mark Pinese, Loretta M S Lau, Dong-Anh Khuong-Quang, Kimberly Dias, Catherine Goudie, Alison Salkeld, Jo Lynne Rokita, David T W Jones, Nikoleta Juretic, Elisha Hayden, Stefan M Pfister, Christof M Kramm, Mirjam Blattner-Johnson, Nada Jabado, Maria Tsoli, Orazio Vittorio, Sabine Mueller, Yiran Guo, Katherine Tucker, Sebastian M Waszak, Sebastien Perreault, Chris Jones, Marie Wong-Erasmus, Mark J Cowley, David S Ziegler.
       BACKGROUND: Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG.
    METHODS: We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n=153), with germline whole genome or whole exome sequencing.
    RESULTS: We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = 0.023). P/LP germline variants were recurrent in homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed near-complete radiological response to PARP and immune checkpoint inhibition.
    CONCLUSIONS: Our study determined the prevalence of pathogenic germline variants in pediatric DMG, and suggests a role in tumorigenesis for a subset of patients.
    Keywords:  PARP inhibitor; diffuse midline glioma; germline variants; homologous recombination; pediatric
    DOI:  https://doi.org/10.1093/neuonc/noaf061
  7. Nat Commun. 2025 Mar 07. 16(1): 2079
    Convection enhanced delivery of Rhenium (186Re) Obisbemeda (186RNL) in recurrent glioma: a multicenter, single arm, phase 1 clinical trial.
    Andrew J Brenner, Toral Patel, Ande Bao, William T Phillips, Joel E Michalek, Michael Youssef, Jeffrey S Weinberg, Carlos Kamiya Matsuoka, Marc H Hedrick, Norman LaFrance, Melissa Moore, John R Floyd.
      Rhenium (186Re) Obisbemeda (186RNL), chelated-186Re encapsulated in nanoliposomes and delivered to brain tumors via convection enhanced delivery (CED), was evaluated in a Phase 1 dose escalation trial (NCT01906385). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included safety and tolerability, dose distribution, the overall response rate (ORR), disease-specific progression-free survival (PFS), and overall survival (OS). 21 patients received up to 22.3 mCi 186RNL over 6 dosing cohorts. Most adverse events (AEs) were unrelated to 186RNL and the MTD was not reached. Although not predefined outcomes, the mOS and mPFS were 11 and 4 months, respectively, and found to correlate with radiation absorbed dose to the tumor and percent tumor treated. When dichotomized by absorbed dose of 100 Gy, the mOS and mPFS were 17 months and 6 months, respectively, for >100 Gy, compared to 6 (mOS) and 2 (mPFS) months, respectively, for <100 Gy. For ORR, 57.1% exhibited stable disease (SD), 4.8% partial response, and 38.1% progressive disease. Overall, patients received radiation absorbed doses without significant toxicity higher than possible with external beam radiation therapy (EBRT) and demonstrated mOS beyond standard of care for recurrent glioblastoma (~8 months).
    DOI:  https://doi.org/10.1038/s41467-025-57263-1
  8. Neuro Oncol. 2025 Mar 14. pii: noaf068. [Epub ahead of print]
    Dual Inhibition of MAPK and TORC1 Signaling Retards Development of Radiation Resistance in Pediatric BRAFV600E Glioma Models.
    Fuyang Li, Kathryn M Bondra, Hanzhou Wang, Dias Kurmashev, Bipasha Mukherjee, Suman Kanji, Amyn A Habib, Yidong Chen, Siyuan Zheng, Sandeep Burma, Peter J Houghton.
       BACKGROUND: MAPK pathway inhibitors (MAPKi) have shown significant efficacy in treating childhood BRAF-activated brain tumors. For tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. MAPKi combining X-radiation therapy (XRT) may improve cure rate, but development of XRT-resistance is a challenge.
    METHODS: XRT-resistance was induced by multiple XRT cycles in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways potentially contributing to XRT-resistance. Cells isolated from PDXs were used to test the contribution of specific genes and pathways to XRT-resistance. PDX models were used to evaluate the efficacy of targeted treatments combined with XRT.
    RESULTS: Tumors developed resistance after multiple cycles of XRT. MEK inhibition combining XRT significantly improved tumor control, compared to XRT alone, but resistance to combined therapy developed rapidly. RNA-sequencing analysis revealed up-regulation of MAPK and PI3K-mTOR signaling in the XRT-resistant tumors. Isolated cells showed in vitro resistance to XRT, which was partially reversed by inhibiting PI3K-mTOR. Up-regulation of TORC1 signaling in XRT naïve tumor cells, via constitutively active AKT or TSC2 deletion, conferred in vitro XRT-resistance.The pro-survival gene BIRC5 (Survivin), a target of TORC1 signaling, contributed to XRT-resistance. Combining trametinib-rapamycin with XRT significantly enhanced therapeutic efficacy in PDX models and prevented or delayed resistance development.
    CONCLUSION: PI3K-mTOR activation promotes the development of XRT-resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT, and can potentially prevent the development of XRT-resistance. (250 words).
    Keywords:  BRAFV600E mutation; MAPK inhibitor; Pediatric Low Grade Glioma (PLGG); X-radiation therapy (XRT); therapeutic resistance
    DOI:  https://doi.org/10.1093/neuonc/noaf068
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