Abstract P5-06-02: Ex vivo CSC assays for personalized testing of drug susceptibility in advanced breast cancer

Abstract

Abstract In the developing area of personalized medicine, targeted therapies are mainly based on genomic characterization of each tumor, and is currently proposed as promising strategies for advanced breast cancer (ABC). Despite the promises of advanced genome sequencing, many patients still fail therapy, resulting in disease progression, recurrence, and metastases. Cancer stem cells (CSCs) concept illustrates the non-genetic intrinsic resistance, recapitulates tumor heterogeneity that creates hierarchically organized tumor tissues where a subpopulation of self-renewing cancer stem cells (CSCs) sustains the long- term clonal maintenance of the neoplasm. Evidences indicate that CSCs survive many commonly employed cancer therapeutics. Patient-derived tumor xenograft (PDXs) models recapitulate tumor complexity and heterogeneity at cellular and molecular level. We aimed to specifically address the therapeutic sensitivity in ABC, by using an ex vivo assay based on PDX prospective collection, fully characterized for genomic alterations. In this work, we aim at defining for each tumor the best therapy to target breast cancer intratumor heterogeneity, the CSC component. For that, we defined a panel of 44 FDA-approved compounds used for cancer treatment, including breast and other types of cancer, cancer stem cell drugs, chemo or targeted therapies. For each drug, we screened the differential sensitivity of the bulk tumor cells and the CSC components for 12 PDX models using an ex vivo screening approach on short term culture. To assess intra tumor heterogeneity, we set up an original dual strategy: for the bulk cells, an ex vivo assay based on IC50, and for breast CSC component a miniaturized Aldefluor assay. First, we demonstrate that bulk cells and CSCs sensitivity may be dissociated for the same drug in the same PDX models. Then, we observed that whereas bulk cell sensitivity may be correlated to tumor genomic abnormalities, CSC drug sensitivity seems not to follow the rule.CSC are selectively sensitive to specific compounds. We are exploring the pathways that sustain this selective sensitivity in the CSCs components. We are currently identifying targets using mass spectrometry in CSCs and bulk cells.Then, we validated the hits predicted from ex vivo screening assays by in vivo treatment of using PDX models for the selected drugs, and in a patient with ABC. In that work, we demonstrated that CSCs display different sensitivity profiles than bulk cells to the same agents, irrespective to their genomic background and are identifying the CSC specific targets. Here, we propose a new model of precision medicine based on ex vivo CSC assays for personalized testing of drug susceptibility in advanced breast cancer. Citation Format: Charafe-Jauffret E, Wicinski J, Cabaud O, Lopez M, Audebert S, Adelaide J, Chaffanet M, Guille A, Goncalves A, Bertucci F, Birnbaum D, Ginestier C. Ex vivo CSC assays for personalized testing of drug susceptibility in advanced breast cancer [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 P5-06-02.