Abstract 205: BBI-608 enhances the activity of chemoradiotherapy in colorectal cancer pre-clinical models

Abstract

Abstract Background: Chemoradiotherapy is a standard treatment modality for early stage rectal cancer (CRC). The pathologic complete response rate after chemoradiation in CRC remains low at 15%. Given the potential for BBI608 to elicit effects on multiple oncogenic cellular pathways, we hypothesized that BBI608 can sensitize colorectal cell lines to the effects of chemoradiotherapy. The aim of this study was to evaluate if BBI-608 enhances the response of chemoradiotherapy against CRC. Methods: The combined effects of BBI-608 and chemoradiotherapy [5-FU + ionizing radiation (IR)] were evaluated in CRC cell lines (HCT 116 and HT-29) using Br-dU cell proliferation and clonogenic assays. Effects on the expression of DNA damage and repair (pATM, pATR, Rad51 and γ-H2AX) molecules and angiogenesis (pSTAT-3 and VEGF) pathways were examined by Western blot. Egg CAM assay was also performed to evaluate effects of the drugs on angiogenesis (quantification was performed by AngioQuant software). The in vivo efficacy of BBI-608 alone or combined with 5-FU + IR, was evaluated in nude mice bearing subcutaneous human HCT116 xenograft tumors Results: The combination of BBI-608 and chemoradiotherapy significantly decreased cell proliferation (p<0.001), colony formation (p<0.001) and inhibited angiogenesis (p<0.001) in CRC cell lines as compared to chemoradiotherapy. BBI-608 decreased angiogenesis as determined by both matrigel plug and egg CAM assays. Immunoblot analysis indicated BBI-608 and chemoradiotherapy also decreased expression of pSTAT-3, MDM2, Rad51 and VEGF while increasing pATM, γ-H2AX and p53, in comparison to chemoradiotherapy alone. In animal models, combined therapy with BBI-608 and 5-FU + IR led to significant inhibition of longitudinal tumor growth as compared to chemoradiotherapy alone (p<0.001). No overt signs of systemic toxicity were evident and animals showed no loss of body weight in any of the treatment groups, indicating the combination was well-tolerated. Conclusion: These observations provide preclinical proof-of-principle data that BBI-608 can enhance the anti-tumor effects of chemoradiotherapy. BBI608 plus chemoradiotherapy is a rational approach for potential future development in early stage rectal cancer. Citation Format: Ganji Purnachandra Nagaraju, Rajitha Balney, Shipra R. Bethi, Sneha Govardhanagiri, Gregory B. Lesinski B. Lesinski, Bassel F. El-Rayes. BBI-608 enhances the activity of chemoradiotherapy in colorectal cancer pre-clinical models [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 205.