Abstract 3309: Novel small molecule ONC201 induces cell death and targets chemotherapy-resistant cancer stem-like cells in triple negative breast cancer

Abstract

Abstract Breast cancer is the most commonly diagnosed cancer in US women today. Triple negative breast cancer (TNBC) accounts for 15% of all breast cancers that are diagnosed and has a poor prognosis. TNBC has a high recurrence rate following treatment with chemotherapy and radiation compared to other breast cancer subtypes. Many tumors, including those of the breast, contain a population of stem-like cells known as cancer stem cells (CSCs). The CSC population is capable of self-renewal and has been shown to be resistant to chemotherapy and radiation. These observations suggest that the CSCs may be responsible for tumor relapse after initial response to therapy. We previously identified a small molecule inducer of the TRAIL pathway, ONC201/TIC10. This compound functions through the ATF4/CHOP pathway to upregulate DR5 (Kline et. al., in press, 2015), and through dual inhibition of Akt/ERK signaling to upregulate TRAIL (Allen et. al Science Translational Medicine, 2013). ONC201 recently completed its first-in-human clinical trial in advanced solid tumors that defined its safety, pharmacokinetics and recommended phase II dose (Stein et al., Abstract C138, 2015 AACR-NCI-EORTC meeting). ONC201 is being tested in multiple phase I/II clinical trials (NCT02250781, NCT02324621, NCT02420795, NCT02392572, NCT02609230, NCT02525692, NCT02038699). We have shown that ONC201 is able to decrease formation of colonospheres as well as deplete colorectal CSC markers in vitro. We have also showed that treatment with ONC201 prevents colorectal CSCs from initiating xenograft tumor growth in mice. (Prabhu et. al Cancer Research., 2015). The goal of this work was to investigate the efficacy of ONC201 in triple negative breast cancer cells, as well as to determine if ONC201 was able to target breast CSCs. We used cell viability assays to determine that the IC50 values for 6 TNBC cell types are in the low micromolar range, doses which are achievable based on human pharmacokinetic data. Propidium iodide staining and analysis of SubG1 DNA content indicates that ONC201 induces apoptosis in TNBC cells. Levels of TRAIL receptor DR5 are increased on the cell surface in TNBC cells following ONC201 treatment. In addition we show that ONC201 is well tolerated and efficacious in vivo against the MDA-MB-231 TNBC xenograft model. We have observed that ONC201 depletes Aldefluor+ TNBC cells in vitro. ONC201 inhibits formation of mammospheres from TNBC CSC-like cells while paclitaxel, a chemotherapeutic drug used to treat TNBC, does not. Our findings suggest that ONC201 exerts cytotoxic effects against TNBC cell types and that ONC201 may target paclitaxel resistant CSCs. Our work contributes to the development of a preclinical rationale for the use of ONC201 as a novel therapy for triple negative breast cancers. Citation Format: Marie D. Baumeister, Jessica Wagner, Varun V. Prabhu, Christina LB Kline, Bora Lim, Josh E. Allen, David T. Dicker, Wafik S. El-Deiry. Novel small molecule ONC201 induces cell death and targets chemotherapy-resistant cancer stem-like cells in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3309.