Abstract 44: PDX-derived cellular models for pharmacological screening and functional studies

Abstract Despite substantial advancements in understanding the biology and genetics of cancer, the development of effective therapies is hindered by the lack of adequate experimental models that replicate the genetic diversity of this disease. Patient-derived xenografts (PDXs) have become the gold standard in preclinical oncology for the evaluation of new anticancer drug candidates. The faithful reproduction of patients' cancer features, and the ability to generate models that recapitulate the genetic heterogeneity of the patient population, confer PDXs with a critical added value in the preclinical field. Over the past 15 years, we have generated and characterized a collection of over 200 PDXs from various solid tumors that accurately reproduce the histological and molecular heterogeneity of original tumors. This panel has enabled the preclinical validation of several anticancer drugs that are now used in the clinic. Although an indispensable tool for conducting preclinical studies, the use of in vivo PDX systems for large-scale screening during early drug discovery is restricted by ethical, economic, and throughput limitations that limit the number of drug candidates tested. To address this challenge, we have developed a panel of PDX-derived cells (PDXDCs) that we propose as a time- and cost-effective, medium-throughput screening tool to profile the anticancer activity of early test compounds. To date, over 50 PDXDCs from various indications such as breast, prostate, lung, and several others have been generated and tested for their in vitro response to standard of care, targeted anticancer agents, and immunotherapies, used as monotherapy or in combination to study potential synergistic effects. PDXDCs were obtained from dissociated PDX tumors cultured under various media and matrix conditions. They were characterized by comparison with the parental PDX through short tandem repeat (STR) profiling prior to establishing a master bank. PDXDC 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 readouts, we could phenocopy in vitro the corresponding PDXs' sensitivities to drug candidates. These results support our PDXDCs panel as a valuable in vitro tool for drug screening to help selecting drug candidates for further in vivo validation, as well as the most appropriate in vivo PDX models to use. Citation Format: Léa Sinayen, Enora Le Ven, Emilie Indersie, Ester Morgado, Laurent Pouyet, François Romagné, Olivier Déas. PDX-derived cellular models for pharmacological screening and functional studies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 44.