Abstract A037: Histone deacetylase inhibitors as emerging therapeutic strategies for glioblastoma and other brain tumors

Abstract Brain tumors, particularly high-grade gliomas such as glioblastoma multiforme (GBM), remain among the most aggressive and treatment-resistant malignancies. Their poor prognosis is driven by extreme cellular heterogeneity, rapid proliferation, infiltrative growth, and the presence of therapy-resistant cancer stem cells (CSCs). Increasing evidence highlights a central role for epigenetic dysregulation—especially abnormal histone deacetylase (HDAC) activity—in tumor initiation, progression, and therapeutic resistance. HDAC overexpression, particularly HDAC1, HDAC2, HDAC6, and several SIRT family members, is frequently observed in GBM and correlates with tumor aggressiveness, metabolic plasticity, and enhanced survival signaling. Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutic agents capable of targeting multiple malignant features simultaneously. Preclinical studies demonstrate that HDACi can reduce CSC viability, promote apoptosis and autophagy, induce cell-cycle arrest, and impair angiogenesis and tumor invasion. HDACi also modulate pathways such as STAT3, SIRT, and SHH, thereby disrupting essential networks that support glioma growth. Importantly, several HDAC inhibitors have demonstrated the ability to cross the blood–brain barrier, increasing their potential for use in primary brain tumor therapy. Furthermore, combining HDACi with radiotherapy or chemotherapy has shown synergistic effects, improving tumor sensitivity and overcoming resistance mechanisms. Although current clinical progress is preliminary, accumulating data suggest that HDAC inhibitors may represent a valuable addition to future multimodal strategies for GBM and other central nervous system tumors. Continued investigation is needed to optimize their therapeutic integration and identify the most responsive patient populations. Citation Format: Laila T A. Metwaly. Histone deacetylase inhibitors as emerging therapeutic strategies for glioblastoma and other brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A037.