bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–11–02
six papers selected by
Oltea Sampetrean, Keio University
  1. Screening of targets related to amino acid metabolism in glioma to identify the tumor-promoting effects of its core gene ASL.
  2. PEAKS activation by PROTAC EPIC-0726 potentiates temozolomide in glioblastoma via K63/K48 ubiquitination-dependent ERK/AKT suppression and p21 stabilization.
  3. Current State-of-the-Art Animal Models of Pediatric Brain Tumors.
  4. Keeping Wnt in check for efficient checkpoint blockade in glioblastoma.
  5. Modulation of the blood-brain barrier permeability by patient-derived glioblastoma stem cell secretome.
  6. Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells.
  1. Sci Rep. 2025 Oct 31. 15(1): 38161
    Screening of targets related to amino acid metabolism in glioma to identify the tumor-promoting effects of its core gene ASL.
    Shisong Wang, Jun Lu, Jingyou Li, Zihao Yan, Zhongxue Yu, Lian Chen, Chen Zhu, Jingyu Zou.
      Gliomas, notably high-grade variants, dominate the spectrum of central nervous system (CNS) malignancies, characterized by aggressive behavior and diffuse invasion. Despite advances in tumor immunology, patient outcomes are stagnant. Amino acid metabolism is pivotal in glioma progression, driving the quest for metabolic targets. Bioinformatics allows deep dives into large-scale patient data from TCGA, CGGA, and GEO. Comparative studies on glioma amino acid metabolism have identified genes associated with tumor characteristics and patient survival. This yields an amino acid metabolism-based risk score model, which elucidates key biological processes and signaling pathways. Our holistic strategy clarifies amino acid metabolism's role in glioma onset, paves the way for targeted therapies. Precise analysis and strategic targeting of metabolic pathways hold great promise for improving glioma treatment, offering hope to patients battling this relentless CNS malignancy.
    Keywords:  ASL; Amino acid metabolism; Glioma; NF-κB
    DOI:  https://doi.org/10.1038/s41598-025-22105-z
  2. Neuro Oncol. 2025 Oct 27. pii: noaf253. [Epub ahead of print]
    PEAKS activation by PROTAC EPIC-0726 potentiates temozolomide in glioblastoma via K63/K48 ubiquitination-dependent ERK/AKT suppression and p21 stabilization.
    Biao Hong, Dongyuan Su, Xiaoteng Cui, Jixing Zhao, Qixue Wang, Qi Zhan, Eryan Yang, Shixue Yang, Jiasheng Ju, Yanping Huang, Chunchao Cheng, Yaqing Ding, Hanyi Xu, Longtao Cui, Yilin Zhao, Xun Zhao, Siwen Liang, Yuhao Liu, Chunsheng Kang.
       BACKGROUND: Despite advances in small-molecule inhibitors (SMIs), the clinical outcomes for glioblastoma (GBM) remain bleak. Recently, polymerase I and transcript release factor (PTRF/Cavin1) has emerged as a promising therapeutic target, with its inhibitor EPIC-1042 demonstrating preclinical anti-tumor activity. However, the therapeutic limitations of SMIs necessitate alternative strategies to achieve enduring target suppression.
    METHODS: EPIC-0726, a proteolysis-targeting chimera (PROTAC) degrader of PTRF, was developed through computer-aided drug design (CADD). Target engagement and degradation specificity were validated by Western blot. Quantitative proteomics identified downstream effectors, while mechanistic insights were elucidated through co-immunoprecipitation, immunofluorescence, and ubiquitination profiling. Orthotopic GBM models were used to assess therapeutic efficacy and temozolomide (TMZ) sensitization.
    RESULTS: EPIC-0726 induced dose-dependent PTRF degradation via the ubiquitin-proteasome system (UPS), requiring ternary complex formation. Proteomic analysis revealed RBX1, a core component of E3 ligase complexes, as a key downstream target. PTRF degradation by EPIC-0726 destabilized RBX1, concurrently suppressing K63-linked ubiquitination-mediated ERK1/2/AKT activation and stabilizing p21 via impaired K48-dependent proteasomal degradation. In vivo, EPIC-0726 monotherapy inhibited GBM growth and synergized with TMZ, with effects more potent than that of EPIC-1042.
    CONCLUSION: This study establishes PROTAC-mediated PTRF degradation as a mechanistically distinct manner to activate proteolysis strategy-enhanced temozolomide efficacy by ERK1/2/AKT kinase suppression and p21 stabilization (PEAKS) through the PTRF-RBX1 regulatory axis. The superior efficacy of EPIC-0726 over EPIC-1042, particularly in overcoming TMZ resistance, provides a paradigm-shifting therapeutic approach for GBM. Our findings warrant the clinical translation of EPIC-0726 as both a monotherapy and a backbone for combination regimens.
    Keywords:  PEAKS; PROTAC; PTRF-RBX1 axis; TMZ efficacy; polyubiquitination modification
    DOI:  https://doi.org/10.1093/neuonc/noaf253
  3. Brain Sci. 2025 Oct 14. pii: 1104. [Epub ahead of print]15(10):
    Current State-of-the-Art Animal Models of Pediatric Brain Tumors.
    Tanusri Gudavalli, Fred C Lam, Santosh Guru, Deyaldeen AbuReesh, Yusuke S Hori, Susan Hiniker, David J Park, Steven D Chang.
      Brain tumors are unfortunately the most common types of solid tumors in the pediatric population, superseded only by leukemias, and largely bode a poor prognosis. Despite advances in our ability to diagnose and treat pediatric brain tumors, there remains a large unmet need to develop novel therapies to improve patient outcomes. The recent understanding of the molecular drivers of oncogenesis for many of these tumors has led to the engineering of preclinical small animal models which serve as valuable tools for scientists to study the mechanisms of tumor biology, to understand interactions with the tumor microenvironment, and allow for translatable novel therapeutic discovery. This review focuses on the state-of-the art development of preclinical models of two difficult-to-treat pediatric brain tumors: (1) diffuse midline gliomas, the most lethal form of pediatric brain cancer; (2) medulloblastoma, the most common embryonal tumor of the central nervous system. We will then round off this review with a discussion on the emerging use of multi-omics and AI approaches to complement the testing of novel therapies using these in vivo animal models.
    Keywords:  medulloblastomas; midline gliomas; mouse models; neuro-oncology; neurosurgery; patient-derived xenografts; pediatric brain tumors
    DOI:  https://doi.org/10.3390/brainsci15101104
  4. Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2523639122
    Keeping Wnt in check for efficient checkpoint blockade in glioblastoma.
    Marit Melssen, Anna Dimberg.
      
    DOI:  https://doi.org/10.1073/pnas.2523639122
  5. Sci Rep. 2025 Oct 27. 15(1): 37437
    Modulation of the blood-brain barrier permeability by patient-derived glioblastoma stem cell secretome.
    Francesco Saverio Sica, Michela Patrucco, Martina Giambra, Martina Ghizzi, Silvia Sesana, Barbara Vergani, Biagio Eugenio Leone, Andrea Di Cristofori, Carlo Giorgio Giussani, Gabriella Nicolini, Angela Bentivegna, Francesca Re.
      The blood-brain barrier (BBB) is a highly selective barrier that strictly controls the passage of substances and cells into the brain, protecting it from potential harm while preserving homeostasis. It is composed of specialised endothelial cells (ECs), along with surrounding cells, such as pericytes and astrocytes. In glioblastoma (GBM), the most prevalent primary malignant brain tumour in adults, the BBB is heterogeneously dysfunctional. In the tumour microenvironment, regions enriched with glioblastoma stem cells (GSCs) are protected by an intact BBB. However, the influence of GSCs on BBB function remains largely unexplored. In this study, the impact of patient-derived GSC (PD GSC) secretomes on human brain capillary ECs has been investigated in vitro. Results showed that secretomes decrease the BBB permeability, leading to an increase of transendothelial electrical resistance and of tight junction protein claudin-5 (CLDN5) levels. Moreover, the receptor for advanced glycation endproducts (RAGE), which is involved in cancer and chemotherapy resistance, modulates CLDN5 expression by activating the pERK/ERK signaling pathway and influences junctional organization. These findings suggest a functional pathway through which PD GSC secretomes can modulate BBB permeability, potentially impacting therapeutic efficacy.
    Keywords:  Blood–brain barrier; Chemoresistance; Endothelial permeability; Glioblastoma; Glioblastoma stem cells; Tight junctions
    DOI:  https://doi.org/10.1038/s41598-025-21272-3
  6. Cancer Metab. 2025 Oct 29. 13(1): 43
    Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells.
    Han Shen, Quy-Susan Huynh, Faiqa Mudassar, Cecilia Chang, Brian Gloss, Prunella Ing, Shiyong Ma, Harriet Gee, Eric Hau, Kristina M Cook.
      
    Keywords:  DIPG; DMG; Dichloroacetate; Diffuse intrinsic pontine gliomas; Diffuse midline gliomas; Lactate; Metabolism; Mitochondria; Oxidative phosphorylation; Phenformin; Radiation
    DOI:  https://doi.org/10.1186/s40170-025-00411-4
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