Abstract B64: Targeting the pH regulators in the tumor microenvironment for ovarian cancer treatment

Abstract

Abstract The high mortality rate in ovarian cancer (OVCA) is currently the most pressing concern despite the research advancements. It is still not clear how to effectively treat OVCA patients to prevent a relapse or to treat the relapse tumors that display a drug-resistant profile. To address this issue, this study targets a uniquely expressed pH regulator in the tumor microenvironment as a strategy to treat ovarian cancer. In order to survive the metabolic acidosis, cancer cells overexpress pH regulators on their surface to pump out excess protons/lactic acid. This, in turn, acidifies the tumor microenvironment and promotes tumor invasion/chemoresistance. The a2-Vacuolar-ATPases (V-ATPases) are the major pH-sensing unit of the V-ATPase proton pumps and are abundantly expressed on the surface of ovarian cancer cells. To establish the clinical importance, our findings show that a2-V-ATPases are overexpressed in all morphologic subtypes and stages of human OVCA and are absent on normal ovarian tissues. We further examined the therapeutic potential of monoclonal antibody against a2-V-ATPase (V0a2-mab) in controlling tumor growth in the preclinical mouse model. In vivo V0a2-mab treatment (300μg in PBS; i.p) resulted in a significantly delayed tumor growth compared to control, with no apparent in vivo toxicity in athymic nude mice xenograft model. The delayed tumor growth was attributed to high immune infiltration with increased leukocyte population and an enhanced iNOS expression compared to control mice. These results show that V-ATPases are overexpressed in the tumor microenvironment and their inhibition impairs OVCA growth by interfering with tumor acidification that enhances the antitumor responses. In conclusion, the study demonstrates that targeting V-ATPase pH regulators is an effective treatment strategy in ovarian cancer. Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Sylvia Schneiderman, Valerie E. Riehl, Alexandria N. Young, Shayna Levine, Safaa Ibrahim, Mahmood Bilal, Alice Gilman-Sachs, Kenneth D. Beaman. Targeting the pH regulators in the tumor microenvironment for ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B64.