Abstract 1929: Establishment, molecular and pharmacological profiling of novel prostate cancer-derived xenografts from patients with advanced, treatment-refractory, disease to identify resistance mechanisms and new therapeutic options

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. The normal development, growth and function of the prostate and most of its malignancies are under androgen regulation. However, after initiation of androgen deprivation therapy (ADT), most patients progress to intractable castration-resistant PCa (CRPC) within 2 to 3 years. Therefore, understanding the mechanisms of resistance that cause PCa to progress to a castration-resistance stage is the key to developing future beneficial therapies. Patient Derived Xenografts (PDX) mouse models show greater fidelity to the disease than any other in vivo models in terms of histopathologic, genomic and metastatic features, facilitating the translation of preclinical results into the clinical setting. However, PCa PDXs have been challenging to develop and a major limitation in PCa research is the lack of relevant preclinical models. The development of PCa PDX models is a mandatory requirement to explore new treatments targeting castration-resistant tumor cells and to improve anti-androgen therapies. To overcome the limitations of the number of relevant available models, in the framework of the MATCH-R clinical trial, which enrolls patients with oncogene-driven cancer who had previously responded to targeted therapy and subsequently experienced disease progression, XenTech and Gustave Roussy Institute are collaborating to develop a panel of extensively characterized PCa PDX models. Using biopsy material from metastatic lesions implanted into the sub-renal capsule of NSG mice, we report the successful establishment of 8 advanced PCa PDX models. All PDX models are characterized at the molecular level by whole exome sequencing and RNA-sequencing. Their response to physical castration and to the androgen receptor inhibitor enzalutamide is compared to the response observed in patients. This collection of PCa PDX models will be a useful preclinical tool to identify pivotal mechanisms underlying acquired resistance to current targeted therapies and develop novel treatment strategies. Citation Format: Olivier Deas, Ludovic Bigot, Emilie Dasse, Fabrice Andre, Jean Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Luc Friboulet, Jean Gabriel Judde, Yohan Loriot. Establishment, molecular and pharmacological profiling of novel prostate cancer-derived xenografts from patients with advanced, treatment-refractory, disease to identify resistance mechanisms and new therapeutic options [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1929.