Abstract 3113: Molecular and pharmacological profiling of a novel prostate cancer-derived xenograft panel to identify resistance mechanisms and new therapeutic options

Abstract

Abstract Prostate Cancer (PCa) is the most frequently diagnosed cancer in men and remains one of the leading causes of cancer death worldwide. It is a highly heterogenous and complex disease, presenting serious challenges to preclinical drug development and biomedical research. Prostate normal development, growth and function, as well as most of its pathological drifts, are associated to androgen receptor (AR) pathway regulation. Most patients subjected to androgen deprivation therapy (ADT) respond well to the treatment, however they usually progress into intractable castration-resistant PCa (CRPC) within 2 to 3 years. Therefore, understanding the mechanisms of castration resistance underlying PCa progression is key to develop future therapies. Patient-Derived Xenografts (PDX) are mouse models that recapitulate the disease more faithfully than any other in vivo model in terms of histopathologic, genomic and metastatic features, facilitating the translation of preclinical results in the clinical setting. PCa PDXs are challenging to develop, and only few are available to the scientific community. This lack of relevant preclinical models is a major limitation in PCa research. In particular, the development of PCa PDX models from castration-resistant tumors to explore new treatments against CRPC is a requirement. To fill this gap, XenTech and Gustave Roussy Institute are collaborating to develop a panel of PCa PDX models. In the framework of the MATCH-R clinical trial (NCT02517892), in which patients with disease progression under treatment are enrolled and switched to new targeted therapy based on the genetic alterations identified in biopsies, 8 PCa PDXs have been developed from metastatic lesions biopsy. In addition, we developed a PCa PDX model from circulating tumor cells (CTCs) obtained by leukapheresis at diagnosis. These 9 models, plus 4 PCa PDXs previously developed at XenTech, increases our PCa PDX panel to 13 models. All models were characterized at molecular level by whole exome and RNA sequencing and pharmacologically for response to standards of care, physical castration and response to the androgen receptor inhibitor enzalutamide. This PDX collection is a valuable preclinical tool to identify pivotal mechanisms underlying acquired resistance to current therapies and develop novel treatment strategies against PCa and CRPC. Citation Format: Laura Brulle-Soumare, Ludovic Bigot, Katell Mevel, Enora Le Ven, Luc Friboulet, Benjamin Besse, Françoise Farace, Jean Gabriel Judde, Stefano Cairo, Yohann Loriot, Olivier Déas. Molecular and pharmacological profiling of a novel prostate cancer-derived xenograft panel to identify resistance mechanisms and new therapeutic options [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 3113.