Anti-Tumor Effects Of Imipridone Onc201 In Combination With Anti-Angiogenic Agents Significantly Impact On Colorectal Cancer Growth In Vivo

Small molecule imipridone ONC201 is an investigational anti-tumor agent with a wide therapeutic index and broad-spectrum efficacy in vivo. ONC201 upregulates intratumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 as therapy in advanced cancer patients has been completed and the drug has progressed into several Phase II trials in multiple cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease continues to have a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. Bevacizumab is a humanized monoclonal antibody that targets VEGF and is an FDA-approved treatment for advanced CRC patients, in addition to other tumor types. We are investigating the potential combination of VEGF inhibitors such as bevacizumab and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) studies. Our results demonstrate significant tumor regression and occasional tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC-38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Non-invasive angiogenesis imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. With the use of both a murine VEGF inhibitor in syngeneic models, and bevacuzimab in human cell line-derived xenografts, we have demonstrated that combining anti-angiogenic therapies with ONC201 could enhance antitumor efficacy. Thus, ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising combinatorial approach that may be exploited in the clinic for the treatment of CRC. Citation Format: Jessica Wagner, Wafik El-Deiry. Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1102. doi:10.1158/1538-7445.AM2017-1102