PATH-87. Distinct cytotoxic effect of polybrene on glioblastoma subtypes

Abstract Glioblastoma, the most aggressive brain tumor, has poor patient prognosis partly due to its high intra-tumoral heterogeneity. This heterogeneity leads to high cellular plasticity and distinct behavior across subtypes, influencing treatment resistance and outcomes. Key molecular features, such as IDH1/2 mutations, high G-CIMP status, and 1p/19q co-deletion, correlate with survival, while IDH-wild-type, lower-G-CIMP status, and intact 1p/19q tumors represent the most aggressive majority. Transcriptomic profiling identifies four dynamic subtypes: neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like), and mesenchymal-like (MES-like). MES-like cells, which are characterized by high plasticity and stem-like features, resist chemotherapy (e.g., temozolomide), while NPC-like cells, being differentiated, are more sensitive. Current subtyping relies on transcriptomics, which is costly and time consuming for clinical use. In this study we propose polybrene, a cationic polymer (hexadimethrine bromide), as a cost-effective tool to distinguish glioblastoma subtypes. Polybrene selectively induces cytotoxicity in chemotherapy-sensitive NPC-like cells via calcineurin activation, a calcium and calmodulin-dependent serine/threonine protein phosphatase, while sparing resistant MES-like cells. These findings highlight polybrene’s potential to provide a rapid, low-cost glioblastoma subtyping profiling method, which could enable personalized therapeutic strategies by targeting subtype-specific vulnerabilities. This approach could streamline clinical decision-making, improving treatment efficacy and patient outcomes in glioblastoma management.