Advanced ovarian cancer (stages III and IV) is the most lethal gynecologic malignancy in the United States. Survival of this cancer has not improved to a major extent over the past decade. High-grade serous ovarian cancer (HGSC), in particular, is notable for its initial sensitivity to chemotherapy using platinum and taxane combination following debulking surgery. However, the vast majority of these cancers (>75-80%) recur within 12-24 months after diagnosis, and patients die of progressively chemotherapy-resistant disease. The identification of prognostic or predictive markers, for ovarian cancer is crucial to the development of therapeutic targets and thus improvement of survival. ONC201 is the first clinical bitopic antagonist of dopamine receptor D2 (DRD2), that is well tolerated and currently being investigated in several clinical trials for oncology. ONC206 is a chemical derivative of ONC201 with the same impridone core structure, which is also a DRD2 antagonist that exhibits distinct receptor pharmacology and nanomolar potency in various preclinical cancer models. However, the effects of ONC206 on HGSC progression and the mechanism of action have not been thoroughly explored. Preliminary data demonstrated that overexpression of DRD2 is associated with poor overall survival rates in patients with advanced stage HGSC. ONC206-treated HGSC cells demonstrated significantly lower growth rates and higher percentage of apoptotic cells than ONC201-treated cells did in vitro. Besides, intraperitoneal injection of ONC206 (100 mg/kg) twice a week into HGSC-bearing immunocompetent mice demonstrated decreased tumor volume in vivo. In addition, by using suspension mass cytometry with a panel of 28 antibodies, fresh tumor tissues from ONC206-treated mice showed markedly increase in intratumoral NK cells and activated CD8+ T cells densities. These data suggest that ONC206 is more potent than ONC201 in suppressing HGSC growth directly. In addition, ONC206 may also suppresses HGSC growth through activating immune cell response in tumor tissues. Further studies that define the molecular mechanism by which DRD2 modulates the tumor suppressive effect of ONC206 on HGSC cells by suppressing HGSC directly or enhancing anti-tumor immune cell activity will be perform to establish ONC206 as a novel therapeutic agent in treatment of HGSC patients.

Citation Format: Chi Lam Au Yeung, Wen Hu, Sammy Ferri-Borgogno, Rohinton S. Tarapore, Joshua E. Allen, Karen H. Lu, Samuel C. Mok. Novel imipridone ONC206 suppresses ovarian cancer progression through modulating immune cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1440.