Objectives: ONC201 is an orally bioavailable dopamine receptor D2 antagonist that induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and TRAIL has been implicated in both the physiopathology of ovarian cancer (OC) and obesity. In addition, DRD2 is a G protein-coupled receptor that activates the trimeric G-protein complex Ras, modulating downstream metabolic pathways such as Akt-signaling which is highly dysregulated in both obesity and OC. ONC201 has demonstrated anti-tumorigenic activity in solid tumors, including uterine serous carcinoma, without significant toxicity in phase 1/2 trials. Thus, we sought to evaluate the anti-tumorigenic effects of ONC201 in human ovarian cancer (OC) cell lines and a high grade serous OC mouse model (K18-gT121+/-;p53fl/fl;Brca1fl/fl; KpB), using both obese and lean mice.
Methods: The human epithelial OC cell lines (OVCAR3, SKOV3, IGROV, OVCAR433, and OVCAR5) were treated with ONC201 at doses of 0.01 to 250 μM. Cell proliferation and apoptosis were assessed by MTT and Annexin V assays, respectively. Adhesion and invasion were assessed by laminin and wound healing assays, respectively. For our animal study, we utilized the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) high grade serous OC mouse model. KpB mice were fed either a low fat diet (LFD, lean) with 10% calories from fat, or a high fat diet (HFD, obese) with 60% calories from fat in order to mimic diet-induced obesity. Following tumor onset, obese and lean mice were treated with vehicle or ONC201 (130 mg once a week, oral gavage) for 4 weeks (n = 8-10 mice/group).
Results: ONC201 significantly decreased cell proliferation in a dose-dependent manner in all five cell lines, with a range of IC50s between 1 and 10μM. Moreover, ONC201 increased Annexin V expression in a dose-dependent manner in both the SKOV3 and OVCAR5 cell lines (p<0.05). Treatment with ONC201 reduced cell adhesion by 25-30% as well as invasion by 20-25% in both OC cell lines when compared to controls (p<0.05). HFD-fed mice (obese) had tumors that were significantly greater in size as compared to LFD-fed mice (lean) (p<0.05). ONC201 decreased tumor weight/size by 65% in the obese mice and 61% in the lean mice (p<0.01).
Conclusions: ONC201 inhibited cell growth, induced apoptosis and decreased cellular adhesion and invasion in human OC cells. ONC201 was efficacious in reducing ovarian tumor growth in both obese and non-obese KpB mice. These results suggest that ONC201 holds promise as a novel targeted therapy in the treatment of OC.
Citation Format: Allison Staley, Katherine Tucker, Ziwei Fang, Yali Fan, Wenchuan Sun, Yajie Yin, Yingao zhang, Varun Prabhu, Chunxiao Zhou, Victoria Bae-Jump. The dopamine receptor D2 antagonist ONC201 has anti-tumorigenic activity in obesity-driven epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 364.