EXTH-30. PHARMACOKINETICS- AND PHARMACODYNAMICS-BASED EVALUATION OF QUISINOSTAT AS A RADIOSENSITIZER IN PRECLINICAL MODELS OF GBM

Abstract

Abstract Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. Class I HDACs mediate chromatin compaction and are frequently overexpressed in GBM. Hence, 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 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 radiation-sensitizing 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, induced global histone hyperacetylation, elevated DNA damage, cell death and cell cycle arrest. 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), coupled with transcriptomic and pharmacodynamic analyses of tumor tissues. We demonstrate quisinostat is a brain-penetrant molecule that reduces tumor burden in flank and orthotopic models of GBM, and significantly extends survival when administered with radiation. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation for the treatment of GBM.