EXTH-26. EXPLORING THE ROLE OF ANDROGEN RECEPTOR SIGNALING IN GLIOBLASTOMA IN AN ORTHOTOPIC ANIMAL MODEL

Abstract OBJECTIVE Gliomas, particularly glioblastoma which is the most common and deadly type, frequently express androgen receptors (AR). We systematically characterized AR expression in low- and high-grade gliomas to investigate whether disrupting AR signaling with readily available blood-brain-barrier penetrant drugs could improve treatment. METHODS Low- and high-grade glioma samples were stained for AR by immunohistochemistry, with AR-expression correlated to grade and sex. Localization of AR and the influence of dihydrotestosterone (DHT) and anti-androgens in glioblastoma cell line (U251) were determined by immunofluorescence and immunoblot. Building on previous in vitro data, we used an orthotopic AR-positive patient-derived model (RN1) to test the efficacy of seviteronel, a blood-brain-barrier penetrant anti-androgen. RESULTS Two thirds of biopsy samples were positive for AR expression by IHC (n=25/39). AR expression correlated with increasing tumor grade (p<0.05) but was similar between sexes (p=0.94). Anti-androgens enzalutamide and seviteronel prevented DHT-induced nuclear translocation of AR; however, seviteronel did so to a lesser extent, as measured by immunofluorescence and immunoblot. In the mouse model, seviteronel significantly improved survival compared to vehicle (n=12, 36.0 vs 27.5 days, p=0.03), and demonstrated reduced Ki67 expression in tumors at the endpoint (68.9% vs 85.0%, p<0.001). Combining seviteronel with temozolomide limited tumor growth as measured by bioluminescence imaging, but did not significantly extend survival compared to temozolomide alone (n=16, 63.5 vs 56.5 days, p=0.37). Adding seviteronel to radiotherapy did not extend survival compared to radiotherapy alone (n=16, 33.0 vs 39.0 days, p=0.19). CONCLUSIONS Targeting AR signaling with blood-brain-barrier penetrant anti-androgens may represent a promising biomarker-directed therapeutic strategy. The mechanisms underlying the effects of seviteronel are being further investigated through affinity-purification mass spectrometry analysis and CUT&RUN sequencing of untreated and treated glioma cells. Additional animal experiments are underway to examine the role of biological sex and the glioma immune microenvironment on the efficacy of anti-androgens in vivo.