Abstract P3-06-04: Bcl-2 functional converters inhibit tumor growth and metastatic potential in zebrafish xenografts

While potential therapies might have pronounced success in the simplified settings in cell culture medium, many drugs fail or underperform when cancer cells are encased in a complex 3D microenvironment. Although, rat and mouse models will continue to be the gold standard for in vivo data in drug discovery, zebrafish xenograft models have emerged as a powerful model that can quickly and efficiently deliver in vivo drug efficacy data before commitment to expensive and time consuming rodent models. We have discovered several compounds that work as B-cell lymphoma 2 (Bcl-2) functional converters and activate Bcl-2 into a killer instead of its native anti-apoptotic role. In this study, we use a zebrafish xenograft model to evaluate the ability of these compounds to inhibit xenograft tumor growth of Bcl-2 expressing cancer cells, including triple negative breast cancers. Live fluorescent imaging of cancer cells within zebrafish embryos revealed a decrease in cancer cell growth while under treatment of compounds. Furthermore, the agents that converted Bcl-2 into pro-apoptotic protein also inhibited the metastatic potential of the cancer cells. Therefore, this study demonstrates zebrafish xenograft techniques that can be used to quickly and efficiently obtain in vivo drug discovery data. Moreover, we report novel Bcl-2 functional converter compounds that can effectively reduce xenograft tumor growth and its ability to invade tissue in a living 3D environment and establish the role of Bcl-2 in cancer progression. Citation Format: Gamble J, Pearce M, Kopparapu P, Jang HS, Tanguay R, Greenwood J, Kolluri S. Bcl-2 functional converters inhibit tumor growth and metastatic potential in zebrafish xenografts [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-06-04.