Abstract 4478: High-throughput dynamic BH3 profiling identifies active cancer therapies in solid tumors
Authors: Bhola Patrick D. , Ahmed Eman , Guerriero Jennifer , Sicinska Ewa , Su Emily , Ni Jing , Lavrova Elizaveta , Chipashvili Otari , Hagan Timothy , Ng Kimmie , Aguirre Andrew , Lorch Jochen , George Suzanne , Demetri George , Zhao Jean , Letai Anthony 
Published: August 2019

Phenotypic differences between primary patient tumors and models of tumors that are amenable to chemical screening represents a key barrier to drug discovery and drug repurposing. High-throughput technologies that can accurately identify active drugs using primary patient tumors are therefore valuable additions to the drug development toolbox and may have direct clinical utility as predictive biomarkers. Here we report a method called high-throughput dynamic BH3 profiling (HT-DBP), a robust microscopy-based assay with single-cell resolution that enables chemical screens of hundreds of candidate drugs on freshy isolated tumor cells to identify chemical inducers of mitochondrial apoptotic signaling. HT-DBP requires only 24 hours of ex vivo culture which enables the direct study of fresh primary tumor cells and minimizes adaptive changes that occur with prolonged ex vivo culture.

Using 1650 compounds, we performed HT-DBP on freshly isolated cells from the MMTV-PyMT genetically engineered mouse model of breast cancer to identify drugs that sensitize these tumors for apoptosis. Selected compounds identified by HT-DBP induced regressions in the MMTV-PyMT genetically engineered mouse model of breast cancer in vivo, and in a patient derived xenograft model of breast cancer. To evaluate how chemical vulnerabilities evolve in cell culture, we performed HT-DBP on a cancer cell line from MMTV-PyMT tumors. We observe different patterns of chemical vulnerabilities between freshly isolated tumor cells and in the derived cell lines, which is consistent with the mixed track record of cancer cell line chemical screens.

We demonstrate that HT-DBP can be used to generate personalized apoptotic chemical vulnerabilities (which we refer to as pharmacotypes) for a set of colon cancer PDX models. We find that a PDX model derived from a primary site tumor and a metastatic lesion from the same patient have different pharmacotypes. Using annotations of small molecule targets, we can identify proteins and signaling pathways that represent apoptotic vulnerabilities in colon PDX models. Finally, we apply HT-DBP to primary human thyroid tumors and sarcomas to identify potential active therapies. In sum, HT-DBP can efficiently predict therapeutic sensitivity upon short-term ex vivo drug exposure and may empower functional precision medicine approaches in the clinic.

Citation Format: Patrick D. Bhola, Eman Ahmed, Jennifer Guerriero, Ewa Sicinska, Emily Su, Jing Ni, Elizaveta Lavrova, Otari Chipashvili, Timothy Hagan, Kimmie Ng, Andrew Aguirre, Jochen Lorch, Suzanne George, George Demetri, Jean Zhao, Anthony Letai. High-throughput dynamic BH3 profiling identifies active cancer therapies in solid tumors [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 4478.