ODM-207: A novel BET bromodomain inhibitor with antitumor activity in nonclinical models of ER+ breast cancer

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Background: The bromodomain and extraterminal (BET) family of proteins are chromatin readers that promote the transcription of several important cell identity genes. BET inhibitors have shown promising antitumor activity in a variety of pre-clinical cancer models, as BET inhibition abrogates the transcription of several key oncogenes in a cell type-specific manner. Hence, the purpose of this study was to determine the anticancer activity of the novel BET inhibitor ODM-207 in ER+ breast cancer models and to look for cancer-associated signaling pathways suppressed by BET inhibitors. 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 analysed 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 and its benzodiazepine-related derivatives. In this study, we show that ODM-207 effectively inhibits the proliferation of ER+ breast cancer cell lines as well as suppresses the growth of patient-derived xenograft tumors. Furthermore, ODM-207 and the JQ1 targeted several pathways important for cancer progression such as the DNA damage and repair pathways. Conclusions: Our results indicate that 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 regulates signaling pathways involved in breast cancer cell survival. Legal entity responsible for the study: Orion Corporation, Orion Pharma. Funding: Orion Corporation, Orion Pharma. Disclosure: A. Moilanen, M. Björkman, R. Riikonen, D. Nicorici, E. Mattila, P. Kallio: Employee: Orion Corporation, Orion Pharma. J. Lindqvist: Employee: Orion Corporation, Orion Pharma, Åbo Akademi University. C. Abbineni, M. Jaleel: Employee: Aurigene Discovery Technologies Limited. J. Eriksson: Employee: Åbo Akademi.

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