Abstract 6913: A preclinical platform of prostate cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies
Authors: Indersie Emilie , Sinayen Léa , Bigot Ludovic , Mevel Katell , Gorse Aurore , Tavernier Marie , Le Ven Enora , Friboulet Luc , Farace Françoise , Morgado Ester , Pouyet Laurent , Loriot Yohann , Romagné François , Déas Olivier 
Published: March 2024

Prostate Cancer (PCa) is the most frequently diagnosed cancer in men and remains one of the leading causes of cancer death worldwide. Despite undeniable progress in understanding the biology and genetics of this highly heterogenous and complex disease, the development of effective therapies is hampered by the lack of relevant experimental models recapitulating its diversity. To tackle this issue, over the last years, we have generated and characterized at the molecular and pharmacology level a collection of prostate cancer patient-derived xenografts (PDX) that accurately reproduce PCa histological and molecular heterogeneity. Although the development of these PCa PDX has been challenging, we are now able to offer a preclinical platform of 11 fully characterized PCa PDX models and in vitro cellular counterparts for preclinical evaluation of novel treatment modalities. Our platform consists of a collection of 4 androgen receptor high (ARPC), 2 androgen receptor low (ARLPC), 1 amphicrine prostate carcinoma (AMPC) and 4 castration-resistant neuroendocrine prostate cancer (CRPC-NE) PDX models and 6 cellular models derived from these PDX (PDXDC). Most of these PDX models were obtained by transplantation of post-surgery tumor specimens either by grafting of tumor fragments in the interscapular region of nude mice or in the subrenal capsule of NOD scid gamma mice. One model is a CTC-derived eXplant established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis injected into the fat pad of NOD scid gamma mice. PDXDC were obtained from dissociated PDX tumors cultured under various media and matrix conditions. They were characterized by comparison with the parental PDX by Short Tandem Repeat (STR) profiling before performing a master bank. All models (PDX and PDXDC) were characterized at molecular level by whole exome and RNA sequencing. PDX were characterized pharmacologically for response to standards of care, physical castration and response to the androgen receptor inhibitor enzalutamide. In vitro drug sensitivity of PDXDC was compared with their parental PDX in vivo drug response. This unique PDX panel reflects the molecular heterogeneity of prostate cancer and reproduces the molecular and drug response profile of human tumors. Associated to in vitro cell derivatives, our collection provides a powerful preclinical platform for translational research to identify mechanisms underlying acquired resistance to current therapies and develop novel treatment strategies against PCa and CRPC.

Citation Format: Emilie Indersie, Léa Sinayen, Ludovic Bigot, Katell Mevel, Aurore Gorse, Marie Tavernier, Enora Le Ven, Luc Friboulet, Françoise Farace, Ester Morgado, Laurent Pouyet, Yohann Loriot, François Romagné, Olivier Déas. A preclinical platform of prostate cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6913.