Abstract 3087: Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis in vivo

Abstract

Abstract ONC201 is a first-in-class small molecule anti-tumor agent (Allen et al., 2013; Wagner et al., 2014; Prabhu et al., 2015; Kline et al., 2015) that upregulates endogenous TRAIL and activates the integrated stress response leading to increased DR5 expression, among other anti-tumor effects. ONC201 recently completed a phase I clinical trial in advanced solid tumors and is currently in multiple phase I/II clinical trials in select advanced cancers (NCT02250781, NCT02324621, NCT02420795, NCT02392572, NCT02609230, NCT02525692, NCT02038699). Colorectal cancer (CRC) remains one of the leading causes of death from cancer worldwide; predominantly due to its metastatic nature. Increasing clinical evidence including randomized clinical trials has demonstrated that there is an increased efficacy from certain cytotoxic chemotherapeutic agents when placed in combination with molecular agents that target the vascular endothelial growth factor (VEGF) pathway. Bevacizumab (Avastin), a monoclonal antibody that targets VEGF, has become an important therapeutic option for patients with advanced metastatic CRC. The single agent activity of ONC201 in preclinical models of colorectal cancer have been well documented, however a combinatorial regimen for this investigational agent has not been prioritized for this indication. We investigated the efficacy of ONC201 in combination with bevacizumab in preclinical models of colorectal cancer based on the previously reported cooperative efficacy with this combination in preclinical GBM models. While each agent showed efficacy as a single agent, the combination of ONC201 with bevacizumab appeared synergistic in the suppression of CRC xenograft growth including a significant impact on tumor regression and occasional complete tumor regressions. The ONC201 combination with bevacizumab also suppressed metastasis from xenografted human colorectal cancer cells. Mechanistic studies and angiogenesis imaging studies are ongoing to demonstrate the importance of this combination on both tumor growth, migration, and invasion. Our results demonstrate that combining anti-angiogenic bevacizumab with ONC201 enhances anti-tumor efficacy in preclinical models of colorectal cancer and suggest that further testing of the combination is warranted in the clinic. Citation Format: Jessica Wagner, Wafik S. El-Deiry. Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis in vivo. [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 3087.