Abstract 4790: Breast cancer stem cells: The next step in the area of personalized medicine
Authors: Emmanuelle Charafe-Jauffret, Christophe Ginestier, Olivier Cabaud, Julien Wicinski, Arnaud Guille, Severine Garnier, Max Chaffanet, Anthony Goncalves, Francois Bertucci, Daniel Birnbaum
Journal: Cancer Research (2016)

Abstract In the developping area of personnalized medicine, targeted therapies are mainly based on genomic characterization of each tumor, and is currently proposed as promising strategies for resistant breast cancer (RBC). 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 RBC, by using a 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 bulk cell sensitivity is often correlated to tumor genomic abnormalities. By opposite, CSC sensitivity seems not to follow the rule and displays selectivively sensitivity to specific targeted compounds belonging to Tyrosine Kinase Inhibitors family. We are exploring the pathways that sustain this selective sensitivity in the CSCs components. Then, we validated the hits predicted from ex vivo screening assays by treating different PDX models for selected drugs. As a Proof-of-concept, we have already validated one CSC targeted strategy for one PDX model. In that work, we demonstrated that CSCs and bulks cells are not sensitive to same treatment, independently to their genomic abnormalities. This result highlights the need for differential testing on the two tumor components, proposes a dual-screening strategy to evaluate the differential drugs sensitivity, validated in PDX models. Afterall, we emphasized the importance of integrating CSC drug sensitivity in the new area of personnalized medicine currently focused on genomic-based strategies and irrespective of intra tumor heterogeneity. Citation Format: Emmanuelle Charafe-Jauffret, Christophe Ginestier, Olivier Cabaud, Julien Wicinski, Arnaud Guille, Severine Garnier, Max Chaffanet, Anthony Goncalves, Francois Bertucci, Daniel Birnbaum. Breast cancer stem cells: The next step in the area of personalized medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4790.