Abstract 1637: PDX-derived cell line platform for pharmacological screening and functional studies

Abstract

Abstract Despite considerable progress in understanding the biology and genetics of cancer, the development of effective therapies is hampered by the lack of sufficient experimental models that recapitulate the genetic diversity of this disease. The recourse to patient-derived xenograft (PDX) for the evaluation of new candidate anticancer drugs is becoming the gold standard in preclinical oncology. The faithful reproduction of patients’ cancer features, and the possibility to generate a large number of models that recapitulate patient population genetic heterogeneity, confer PDXs a critical added value in the evaluation of new candidate drugs. These improved models will hopefully contribute to decrease the attrition rate observed in clinical trials, thus far unacceptably high. Over the last 15 years, we have generated and characterized a collection of 200+ PDXs from different solid tumors that accurately reproduce the histological and molecular heterogeneity of the tumors of origin. This panel has allowed for the preclinical validation of several anticancer drugs that are now used in the clinic. Although being an indispensable tool to complete preclinical studies, the use of PDX in vivo systems for large-scale screening during early drug discovery is hampered by ethical, economical and throughput burdens limiting the number of test articles being tested. To address this problem, we developed a panel of PDX-derived cell lines (PDXDCs) that we propose as a time and cost-effective medium-throughput screening tool to profile the anti-cancer activity of early test compounds. To date, 50+ PDXDCs from various indications such as breast, lung, prostate and many others have been generated and tested for their response in vitro towards standards of care and targeted anti-cancer agents matching patient clinical management. Differently from standard cell line establishment, which is obtained by expansion of a cell clone that survives in vitro plating, our cell line development technology allows for maintenance of tumor cell population heterogeneity. PDXDCs RNA and exome sequencing data faithfully match the parental PDX features, and by modulating experimental parameters, such as 2D or 3D growth conditions, drug exposure duration and endpoint read-outs, we could phenocopy in vitro the corresponding PDXs’ sensitivities to chemotherapies. These results show our PDXDCs panel is a valuable in vitro platform for drug screening to help selecting drug candidates for further validation in parental PDX models in vivo. Citation Format: Olivier Déas, Léa Sinayen, Emilie Indersie, Kathleen Flosseau, Sophie Banis, Enora Le Ven, Jean-Gabriel Judde, Stefano Cairo. PDX-derived cell line platform for pharmacological screening and functional studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1637.