P01.13.A MECHANISMS OF RADIOSENSITIZATION AND RESISTANCE FOLLOWING HDAC INHIBITION IN GBM PRECLINICAL MODELS.

Abstract BACKGROUND Conventional therapies remain ineffective against glioblastoma (GBM), highlighting the need for novel radiosensitization approaches. Histone deacetylase (HDAC) inhibitors demonstrate potential as radiosensitizers, yet clinical applications have been unsuccessful due to limited brain penetration and gaps in understanding response predictors. This study investigates how p53 status influences QST-mediated radiation sensitization in GBM preclinical models and examines adaptive mechanisms potentially contributing to treatment resistance. METHODS We utilized patient-derived GBM models with diverse p53 profiles, including genetically modified and naturally mutant variants, to evaluate QST-mediated radiosensitization both in vitro and in orthotopic models. We measured DNA damage persistence, cellular survival rates, and overall therapeutic effectiveness. Transcriptomic analysis of residual tumor tissue post-treatment identified phenotypic adaptations, which underwent further characterization through functional assays. RESULTS QST achieved sufficient brain concentrations for effective HDAC1/2 inhibition and significantly enhanced radiation sensitivity in p53-wildtype tumors, while p53-mutant GBM models showed minimal response. The radiosensitization effect corresponded with prolonged DNA damage and decreased survival specifically in p53-wildtype tumors. Analysis of post-treatment tumors revealed transitions toward neuronal-like gene expression patterns (including upregulation of GABRA2, GRM3, GRIK2, GLUA4), cytoskeletal modifications (notably β-tubulin upregulation), and downregulation of DNA damage response genes, suggesting adaptive resistance mechanisms. Targeting these pathways in conjunction with QST and radiation therapy may help overcome resistance. CONCLUSION p53 status could be a putative predictive biomarker for HDAC inhibition-mediated radiosensitization in GBM. The identification of treatment-induced neuronal-like adaptations and cytoskeletal alterations provides insights into resistance mechanisms and future drug combination strategies. These preclinical findings will undergo validation through a tissue-based Phase 0/1 trial evaluating QST combined with radiation therapy in both newly diagnosed and recurrent GBM patients (Q2 2025).