bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–08–10
eight papers selected by
Oltea Sampetrean, Keio University
  1. Advancing vaccine-based immunotherapy in glioblastoma treatment.
  2. SCD1 and SCD5 Modulate PARP-Dependent DNA Repair via Fatty Acid Desaturation in Glioblastoma.
  3. Differential Bioenergetic Profile of Human Glioblastoma following Transplantation of Myocyte-derived Mitochondria.
  4. Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression.
  5. Spatial Multi-omics Defines a Shared Tumor Infiltrative Signature at the Resection Margin in High-Grade Gliomas.
  6. Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial.
  7. Angulin-1/LSR inhibition transiently disrupts the blood-tumor barrier to enhance doxil permeability and impair malignant glioma progression.
  8. Virtual Screening-Guided Discovery of Small Molecule CHI3L1 Inhibitors with Functional Activity in Glioblastoma Spheroids.
  1. Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf135
    Advancing vaccine-based immunotherapy in glioblastoma treatment.
    Desh Deepak Singh, Shafiul Haque, Abhishek Kumar Singh, Dharmendra Kumar Yadav.
      Glioblastomas (GBMs) originate from glial cells and are characterized by aggressive growth and poor prognosis. Despite advances in surgical resection, complete elimination remains challenging, often leading to recurrence that is resistant to standard therapies. Immunotherapy and conventional treatments show promise in enhancing therapeutic outcomes across various cancers. Researchers continue to explore new treatments, particularly radiation, chemotherapy, and surgery; however, glioblastoma remains highly challenging, with only modest improvements in survival. Recent progress in immunotherapy, especially with tumor vaccines such as peptide-based and cell-based options (eg, dendritic cell vaccines), represents significant advancements despite the limitations observed in current clinical trials. This article reviews recent developments in vaccine-based immunotherapy for glioblastoma treatment.
    Keywords:  glioblastoma; tumor antigen; vaccine efficacy; vaccine perspective; vaccine platform
    DOI:  https://doi.org/10.1093/noajnl/vdaf135
  2. bioRxiv. 2025 Jul 27. pii: 2025.07.23.666454. [Epub ahead of print]
    SCD1 and SCD5 Modulate PARP-Dependent DNA Repair via Fatty Acid Desaturation in Glioblastoma.
    Hayk Mnatsakanyan, Alessandro Sammarco, Rami Awwad, Abigail Hewett, Elie Roumieh, Caline Pechdimaljian, Yana Azar, Richa Pradhan, Baolong Su, Kevin J Williams, Steven J Bensinger, Christian E Badr.
      Glioblastoma (GBM) relies on fatty acid metabolism to sustain its aggressive growth. While the role of stearoyl-CoA desaturase-1 (SCD1) in GBM is established, the function of its brain-enriched isoform, SCD5, remains unexplored. Here, we demonstrate that SCD5 is essential for glioblastoma stem cell (GSC) maintenance and genomic stability, with elevated expression in GSCs that declines upon differentiation, underscoring its role in tumor initiation. Through shotgun lipidomics, 13 C metabolic flux analysis, and functional genomics, we reveal that SCD1 and SCD5 play non-redundant roles in fatty acid desaturation, with SCD5 preferentially desaturating C18:0 and uniquely contributing to sphingolipid remodeling. Genetic silencing of either isoform disrupts cell cycle progression, impairs DNA damage repair, and reduces GSC viability, while SCD5 knockdown significantly extends survival in orthotopic GBM models. Mechanistically, loss of SCD activity or saturated fatty acid accumulation triggers PARP1 hyperactivation and subsequent degradation, depleting RAD51 to compromise homologous recombination and induce parthanatos. These findings uncover a lipid-mediated vulnerability in GBM, linking fatty acid desaturation to PARP1-dependent genome integrity. Targeting SCD5 may offer a novel therapeutic strategy to eliminate therapy-resistant GSCs and enhance the efficacy of genotoxic or immunotherapeutic interventions.
    DOI:  https://doi.org/10.1101/2025.07.23.666454
  3. bioRxiv. 2025 Aug 01. pii: 2025.08.01.668058. [Epub ahead of print]
    Differential Bioenergetic Profile of Human Glioblastoma following Transplantation of Myocyte-derived Mitochondria.
    Kent L Marshall, Ethan Meadows, Alan Mizener, John M Hollander, Christopher P Cifarelli.
      Glioblastoma (GBM) exhibits profound plasticity, enabling adaptation to fluctuating microenvironmental stressors such as hypoxia and nutrient deprivation. However, this metabolic rewiring also creates subtype-specific vulnerabilities that may be exploited therapeutically. Here, we investigate whether mitochondrial transplantation using non-neoplastic, human myocyte-derived mitochondria alters the metabolic architecture of GBM cells and modulates their response to ionizing radiation. Using a cell-penetrating peptide-mediated delivery system, we successfully introduced mitochondria into two mesenchymal-subtype GBM cell lines, U3035 and U3046. Transplanted cells exhibited enhanced mitochondrial polarization and respiratory function, particularly in the metabolically flexible U3035 line. Bioenergetic profiling revealed significant increases in basal respiration, spare respiratory capacity, and glycolytic reserve in U3035 cells post-transplantation, whereas U3046 cells showed minimal bioenergetic augmentation. Transcriptomic analyses using oxidative phosphorylation (OXPHOS) and glycolysis gene sets confirmed these functional findings. At baseline, U3035 cells expressed high levels of both glycolytic and OXPHOS genes, while U3046 cells were metabolically suppressed. Following radiation, U3035 cells downregulated key OXPHOS and glycolysis genes, suggesting metabolic collapse. In contrast, U3046 cells transcriptionally upregulated both pathways, indicating compensatory adaptation. These results identify and establish mitochondrial transplantation as a metabolic priming strategy that sensitizes adaptable GBM subtypes like U3035 to therapeutic stress by inducing bioenergetic overextension. Conversely, rigid subtypes like U3046 may require inhibition of post-radiation metabolic compensation for effective targeting. Our findings support a novel stratified approach to GBM treatment which integrates metabolic subtype profiling with bioenergetic modulation.
    DOI:  https://doi.org/10.1101/2025.08.01.668058
  4. Nat Commun. 2025 Aug 06. 16(1): 7250
    Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression.
    Leo Carl Foerster, Oguzhan Kaya, Valentin Wüst, Diana-Patricia Danciu, Vuslat Akcay, Milica Bekavac, Kevin Chris Ziegler, Nina Stinchcombe, Anna Tang, Susanne Kleber, Joceyln Tang, Jan Brunken, Irene Lois-Bermejo, Noelia Gesteira-Perez, Xiujian Ma, Ahmed Sadik, Phuong Uyen Le, Kevin Petrecca, Christiane A Opitz, Haikun Liu, Christian Rainer Wirtz, Angela Goncalves, Anna Marciniak-Czochra, Simon Anders, Ana Martin-Villalba.
      The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecasts how tumor cells organize to sustain growth and identifies the rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA-related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt-antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases the overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor's stem-like methylome into an astrocyte-like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.
    DOI:  https://doi.org/10.1038/s41467-025-62528-w
  5. Cancer Res. 2025 Aug 04.
    Spatial Multi-omics Defines a Shared Tumor Infiltrative Signature at the Resection Margin in High-Grade Gliomas.
    Balagopal Pai, Susana Isabel Ramos, Wan Sze Cheng, Tanvi Joshi, Emine Özen, Lakshmi Shree Kulumani Mahadevan, Thenzing J Silva-Hurtado, Gabrielle A Price, Jessica Tome-Garcia, German Nudelman, Sanjana Shroff, Kristin G Beaumont, Raymund L Yong, Robert P Sebra, Elena Zaslavsky, Nadejda M Tsankova.
      Despite genomic heterogeneity, most high-grade gliomas (HGG), including IDH-wildtype glioblastoma, display diffusely infiltrative growth, which impedes complete surgical resection and leads to inevitable recurrence. Understanding of HGG biology comes predominantly from studies using resected "core" tissue. Paradoxically, chemoradiation targets residual disease at the resection margin, which remains poorly defined. To address this, we generated a high-throughput single-nucleus (sn)RNA-seq and snATAC-seq multi-omic dataset from matching "core" and "margin" dissections in four distinct grade 4 HGG (EGFR-amplified, NF1-mutant, FGFR3-TACC3 fused, IDH1-mutant; n= 36,811 snRNA-seq and 30,705 snATAC-seq nuclei after filtering) and combined it with new spatial transcriptomics data from two additional HGG (EGFR-amplified, CDK4-amplifed) to evaluate "core-to-margin" transition. Computational analyses included functional enrichment, comparison to prior HGG datasets, differential analyses in core vs. margin cell types or regions-of-interest for genes, chromatin accessibility peaks, cell-cell interactions, transcription factor motif activity and associated regulon targets, and reconstruction of core-to-margin transition using RNA velocity and pseudotime. Contrasting tumor-specific biology in matching core and margin dissections defined a unique, shared "glioma infiltration" signature near the margin. EGFR was prioritized as a top differentially expressed and accessible tumor margin marker across HGG subtypes that showed dynamic expression along a core-to-margin infiltration trajectory. CRISPR/Cas9-mediated deletion of EGFR in two patient-derived models validated its role in migration, and combined snATAC-seq with ChIP-seq studies suggested a role for TEAD1 as a transcriptional regulator of EGFR at the margin. This multi-omic resource will enable further studies into residual disease biology of tumors and the microenvironment at the infiltrative margin.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4708
  6. J Clin Oncol. 2025 Aug 08. JCO2500618
    Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial.
    Andrew B Lassman, Mei-Yin C Polley, Fabio M Iwamoto, Andrew E Sloan, Tony J C Wang, Kenneth D Aldape, Jeffrey S Wefel, Vinai Gondi, Alonso N Gutierrez, Mohammed H Manasawala, Mark R Gilbert, Erik P Sulman, Jedd D Wolchok, Richard M Green, Elizabeth C Neil, Rimas V Lukas, Samuel A Goldlust, Matija Snuderl, Kristyn Galbraith, James J Dignam, Minhee Won, Minesh P Mehta.
       PURPOSE: New therapies for glioblastoma are needed, especially MGMT-unmethylated (uMGMT) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.
    METHODS: Adults with newly diagnosed uMGMT glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields. With 95% power to detect a hazard ratio (HR) ≤0.58 for progression-free survival (PFS) at a one-sided significance level (P) of .15, superior PFS with immunotherapy in phase II would lead to phase III overall survival (OS) testing. Corticosteroids were disallowed when starting immunotherapy. Diagnosis, biomarkers, and PFS were centrally assessed.
    RESULTS: One hundred fifty-nine participants were randomly assigned (79 immunotherapy and 80 TMZ). Arms were well balanced for age (median 60 years, range, 28-79), sex (male n = 105, 66%), KPS (90-100 n = 97, 61%), resection extent (gross total, n = 103, 65%), and RPA class (III, n = 16, 10%; IV, n = 116, 73%; V, n = 27, 17%). A preplanned analysis of phase II data conducted after 100 centrally determined PFS events showed no significant PFS improvement for ipi and nivo versus TMZ (median 7.7 months v 8.5 months, HR, 1.47 [70% CI, 1.19 to 1.83]; one-sided P = .96 [95% CI, 0.98 to 2.2]). OS is immature (>50% alive) but with no observed difference between arms (median approximately 13 months each, HR, 0.95 [95% CI, 0.61 to 1.49]; P = .36).
    CONCLUSION: Ipi and nivo did not improve PFS among patients with newly diagnosed uMGMT glioblastoma versus TMZ. Accrual closed permanently; the trial will not proceed to phase III. No new safety signals were identified. Molecular correlative analyses and survival follow-up are ongoing.
    DOI:  https://doi.org/10.1200/JCO-25-00618
  7. bioRxiv. 2025 Aug 02. pii: 2025.07.31.667901. [Epub ahead of print]
    Angulin-1/LSR inhibition transiently disrupts the blood-tumor barrier to enhance doxil permeability and impair malignant glioma progression.
    Dominique Ferguson, Minhye Kwak, Sanghee Lim, Melissa Cesaire, Jatia Mills, Mahalia Dalmage, Jane Jones, Sergey Tarasov, Marzena Dyba, Rob Robey, Yanbo Yang, Shae K Simpson, Baktiar Karim, Donna Butcher, Robyn Gartrell, Michael Gottesman, Sadhana Jackson.
      The blood-tumor barrier (BTB) prevents effective central nervous system (CNS) drug delivery, especially in malignant gliomas. Brain endothelium predominates the BTB and connects through bicellular and tricellular tight junctions (TJ). Angulin-1/LSR, is a highly expressed endothelial tricellular TJ. Our studies explore the role of Angubindin-1, an Angulin-1/LSR binder, to disrupt tricellular TJ integrity, increase drug entry and hamper glioma progression. Using rat brain endothelial cells (RBMVEC) we tracked Angulin-1/LSR localization and expression to the membrane; binding tightest to Angubindin-1 2-8 hours post-treatment ( p < 0.05). Angubindin-1 dose-dependently reduced bicellular and tricellular TJs 1-4 hours post treatment ( p < 0.05), returning to baseline by 24 hours ( p < 0.05). In human and rat-derived glioma cells, Angubindin-1 transiently reduced Angulin-1/LSR expression between 2-8 hours ( p < 0.05), with return to baseline by 24 hours ( p < 0.001). Silenced Angulin-1/LSR expression on endothelium resulted in decreased mRNA levels of bicellular (occludin, claudin-5, ZO-1) and tricellular (tricellulin/MARVELD2, angulin-1/LSR) TJs compared to control ( p < 0.01). Angubindin-1 treatment also inhibited efflux transporter P-gp in both RBMVECs and glioma cells with high P-gp expression only. Orthotopic rat glioma models were treated with Doxil (3 mg/kg), Angubindin-1 (10 mg/kg), or combination to evaluate BTB permeability/drug accumulation, and overall survival. Combination therapy enhanced Doxil tumor accumulation by 20% ( p < 0.001), reduced tumor volume by day 14 (77.5% vs. 81.6%, p < 0.05), and significantly extended survival compared to Doxil alone (24 days vs. 18 days, p < 0.0001). These findings demonstrate the effects of tricellular tight junction inhibition on disrupting the BTB, enhancing CNS drug delivery, and improving rodent glioma survival.
    Significance: This study demonstrates that Angubindin-1, a targeted modulator of tricellular tight junction protein Angulin-1/LSR, transiently disrupts BTB integrity to enhance chemotherapy delivery and prolong survival in glioma-bearing rats.
    DOI:  https://doi.org/10.1101/2025.07.31.667901
  8. bioRxiv. 2025 Aug 01. pii: 2025.07.31.667816. [Epub ahead of print]
    Virtual Screening-Guided Discovery of Small Molecule CHI3L1 Inhibitors with Functional Activity in Glioblastoma Spheroids.
    Baljit Kaur, Katrin Denzinger, Longfei Zhang, Nelson Garcia-Vazquez, Gerhard Wolber, Moustafa Gabr.
      Chitinase-3-like protein 1 (CHI3L1), a glycoprotein implicated in inflammation, fibrosis, and cancer, has emerged as a potential therapeutic target for glioblastoma (GBM). CHI3L1 contributes to tumor progression and immune evasion by promoting STAT3 signaling and mesenchymal transition. To identify small molecule CHI3L1 inhibitors, a structure-based 3D pharmacophore model was developed and applied to virtually screen over 4.4 million compounds from the Enamine collection. Following multi-tiered filtering, 35 candidates were selected for experimental evaluation. Binding validation via microscale thermophoresis (MST) confirmed dose-dependent CHI3L1 interactions for two compounds, 8 and 39, with dissociation constants (Kd) of 6.8 μM and 22 μM, respectively. These affinities were further supported by surface plasmon resonance (SPR), which yielded Kd values of 5.69 μM for compound 8 and 17.09 μM for compound 39. In 3D GBM spheroid models, compound 8 significantly reduced spheroid viability and attenuated phospho-STAT3 levels, consistent with CHI3L1 pathway disruption. These findings identify two promising scaffolds and support the utility of pharmacophore-guided virtual screening for discovering functionally active ligands targeting CHI3L1 in GBM.
    DOI:  https://doi.org/10.1101/2025.07.31.667816
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