Abstract 349: Pharmacokinetics- and pharmacodynamics-based evaluation of quisinostat as a radiosensitizer in preclinical models of human glioblastoma

Abstract

Glioblastoma (GBM), the most common and aggressive primary brain tumor affecting adults, is characterized by an aberrant yet druggable epigenetic landscape. Class I histone deacetylases (HDACs) mediate chromatin compaction and are frequently overexpressed in GBM. Hence, over the last decade, there has been considerable interest in HDAC inhibitors (HDACi) for the treatment of malignant brain tumors. However, to date almost all HDACi tested clinically have failed to provide significant therapeutic benefit to primary and recurrent GBM patients. These HDACi are broad-spectrum with poor or unknown pharmacokinetic profiles and have narrow therapeutic window. Isoform specificity for HDACi is important given that not all HDAC enzymes are equally expressed in GBM. Recently, we uncovered the functional importance of HDAC1 in therapy-resistant glioma stem cells, where we found that its expression increases with brain tumor grade and is correlated with decreased survival. While no class I HDAC isoform-specific inhibitors are currently available, the second-generation HDACi, quisinostat harbors high specificity for HDAC1. In this study, we assessed the pharmacokinetic, pharmacodynamic and radiosensitizing properties of quisinostat in preclinical models of human GBM. In vitro analyses conducted in patient-derived glioma stem cell (GSC) lines revealed that quisinostat exhibited potent growth inhibition in multiple GSC lines (IC50 ~ 50-86 nM), and induced global histone hyperacetylation, elevated DNA damage, cell death, cell cycle arrest and decreased expression of multiple key stem cell proteins. To determine the efficacy and drug distribution profile of quisinostat in vivo, athymic mice with orthotopic or flank tumors were treated with an optimized treatment schedule. At various timepoints during treatment, plasma and brain/tumor tissue were collected to measure total and unbound drug levels by liquid chromatography tandem mass spectrometry (LC-MS/MS) and assess pharmacodynamic changes within tumor tissues. We found that quisinostat reduces tumor burden in flank and orthotopic models of GBM and extends survival when administered in combination with radiation therapy in vivo. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation in the treatment of GBM. Citation Format: Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna Melendez, James McNamara, William Knight, Sarah Himes, Connor White, Alexis Giff, Jesus Peralta, Nader Sanai, Artak Tovmasyan, Shwetal Mehta. Pharmacokinetics- and pharmacodynamics-based evaluation of quisinostat as a radiosensitizer in preclinical models of human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 349.