Abstract 820: Combined HDAC and ATM inhibition potentiates anticancer effects in glioblastoma preclinical models

Abstract Background: Brain penetrant histone deacetylase inhibitors (HDACi) are promising radiosensitizing agents for glioblastoma (GBM). In addition to suppression of HDAC activity, the antiproliferative effect of HDACi includes downregulation of DNA damage repair (DDR) pathway and persistent DNA damage. Here, we evaluated synergistic effect of combining HDAC and DNA repair enzyme, ataxia telangiectasia mutated (ATM) inhibitors, quisinostat (QST) and AZD1390 to broaden therapeutic window for GBM treatment. Methods: In vitro dose-response assays were performed in patient-derived xenograft (PDX)-derived glioma stem cells (GSCs) with both QST and AZD1390 with or without radiation treatment to assess synergy. Immunoblotting and immunofluorescence assays were performed for histone acetylation, DNA damage (pH2AX), pRAD50, pATM and cleaved caspase 3 to assess pharmacodynamic responses. Quantitative PCR analysis was performed to examine changes in gene expression of key DNA damage pathway genes. Results: Combined treatment with QST and AZD1390 synergistically inhibit GBM growth across multiple GBM GSC models in combination with radiation. HDACi treatment dampens the DDR response pathway via suppression of key DDR pathway genes resulting in persistent unrepaired DNA damage. Conclusions: Our data indicate that QST and AZD1390 act synergistically to radiosensitize GBM cells and increase the therapeutic window for treatment. In vivo experiments are under way to examine efficacy of this combination using orthotopic PDX GBM models. Keywords: glioblastoma, ATM, HDAC, DNA damage repair Citation Format: Susan J. Histed, Kaitlyn Chung, Gozde Uzunalli, Elizabeth Hayes, Kyria Kelley-Wolfe, Jordan Fakhoury, Tigran Margaryan, Sonam Patel, Nader Sanai, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta. Combined HDAC and ATM inhibition potentiates anticancer effects in glioblastoma preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 820.