PARP Inhibition Shows Anticancer Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) [40E

Abstract

INTRODUCTION: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer characterized by germline and somatic inactivation of SMARCA4. There is urgent need for effective targeted therapy for SCCOHT. METHODS: In silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database that included drug sensitivity data of 265 compounds in 1,074 cancer cells were conducted. Drug sensitivity in ovarian cancer cells with SMARCA4 mutation was analyzed, and further in vitro and in vivo studies were performed using the compound. Animal use was approved by local institutional review board. RESULTS: Two PARP inhibitors (PARPi) and 1 AR inhibitor showed significant selectivity for the 3 ovarian cancer cell lines with SMARCA4 mutation and 2 of which were confirmed SCCOHT cell lines (OVK-18 and TOV-112D). BRCA1/2 or ATM status did not affect selectivity. We validated findings in another two SCCOHT cell lines (BIN-67 and COV434) showing significant inhibition of proliferation with PARPi whereas only trend for inhibition for AR blockade in contrast with OVCAR3 and SK-OV-3 ovarian cancer cell lines that did not harbor SMARCA4 mutation. AR blockade however enhanced effect of PARPi in SCCOHT cell lines. Similar effects of PARPi+/-AR blockade were also observed in apoptosis, epithelial-to-mesenchymal transition, migration and colony formation assays. PARPi and AR blockade inhibited BIN-67 xenograft tumor growth with no remarkable toxicity. CONCLUSION: PARPi plus AR blockade holds promise for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models. Further investigation for clinical translation is warranted.