Abstract 3827: Antitumor activity of ODM-207, a novel BET bromodomain inhibitor, in nonclinical models of ER+ breast cancer as single agent and as a combination treatment

Abstract

Abstract Introduction: The bromodomain and extraterminal (BET) family of proteins are chromatin readers that promote the transcription of several important cell identity genes. BET proteins also control expression of many genes that play an essential role in the pathogenesis of human cancer, including cell-cycle and proliferation-regulating genes. The small-molecule BET inhibitors block BET binding to chromatin and have shown antitumor activity in a variety of pre-clinical cancer models. In this study, we evaluated the anticancer activity of the novel BET inhibitor, ODM-207, in ER+ breast cancer models as a single agent and in combination with other cancer drugs. Methods: ER+ breast cancer cell lines were studied for sensitivity to ODM-207 and the in vivo efficacy was assessed using the ER+ Ma3366 patient-derived xenograft model. For gene expression analyses, breast cancer cells were treated with ODM-207 or reference BET inhibitor JQ1 and differentially expressed genes were analyzed by RNA-sequencing. The ability of ODM-207 to regulate anticancer signaling pathways was validated by western blotting. Synergistic drug interactions were profiled using five-concentration dose response matrices. Results: ODM-207 is a novel BET inhibitor structurally distinct from JQ1 that shows antiproliferative activity in a broad panel of cancer cell lines. The strongest antitumor activity could be observed in hormone-dependent prostate and breast cancer models. In this study, we show that ODM-207 effectively inhibits the proliferation of ER+ breast cancer cell lines by inducing cell cycle arrest in G0/G1-phase. Additionally, ODM-207 suppresses the growth of ER+ patient-derived breast cancer xenograft tumors. ODM-207 as well as JQ1 targeted several pathways important for cancer progression such as MYC, estrogen response and cell cycle gene signatures. The inhibition of key cell cycle regulators, such as CDK4 and Cyclin D1, were further verified. The cyclin D1:CDK4/6 axis plays a significant role in the development, and currently, treatment of ER+ breast cancer together with endocrine therapy. Interestingly, ODM-207 was shown to synergize with palbociclib in vitro in ER+ breast cancer cell lines: the combination of ODM-207 and CDK4/6 inhibitor palbociclib achieved greater cell proliferation inhibition than either drug alone at sub IC50 concentrations. Notably, the ODM-207 and palbociclib combination did not cause the induction of an obvious senescent-like phenotype as compared to palbociclib alone, but rather affected cell survival cellular assays. Conclusions: In summary, ODM-207, which is currently in Phase I clinical trials for treating solid tumors, causes significant growth inhibition in pre-clinical models of ER+ breast cancer and enhances antiproliferative activity of palbociclib, providing a rationale for development of a combination therapy. Citation Format: Julia Lindqvist, Mari Björkman, Reetta Riikonen, Daniel Nicorici, Elina Mattila, Mahaboobi Jaleel, Chandrasekhar Abbineni, Anu-Maarit Moilanen. Antitumor activity of ODM-207, a novel BET bromodomain inhibitor, in nonclinical models of ER+ breast cancer as single agent and as a combination treatment [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 3827.