Abstract 1718: The importance of clinically relevant rapid autopsy specimens and LuCaP patient-derived xenograft models to interrogate the heterogeneous and evolving treatment resistance of castration-resistant prostate cancer

Abstract

Abstract Recent advances in our understanding of metastatic castration-resistant prostate cancer (mCRPC) biology have led to the approval and use of multiple novel drugs, including abiraterone, enzalutamide, cabazitaxel, sipuleucel-T and radium-223. Although these agents all provide improvement in survival, resistance always develops after an initial response. To understand the biology of responses and resistance, clinically relevant specimens and preclinical models are needed. To address this critical need, our objectives are: 1) to collect samples of metastases prior to and after treatment for evaluation of potential biomarkers of responses and resistance and 2) to generate patient-derived xenografts (PDXs) that are representative of these novel phenotypes of advanced mCRPC. A Rapid Autopsy Program (RAP) was established at the University of Washington to study the lethal phenotype of mCRPC. Through the RAP we have collected more than 3000 tissue specimens, including bone and visceral metastases from over 110 patients who died of mCRPC. The samples were processed for paraffin embedding and frozen for future histological and molecular analyses. All samples are tracked in a relational database and cross-linked to clinical and pathologic data. To provide clinically relevant preclinical models for studies of late stage advanced prostate cancer, we also implant tissues acquired during the RAP into immunocompromised mice in order to establish novel CRPC PDXs. At present we have 28 primary PDXs (the LuCaP series), and 10 castration-resistant sublines of the primary lines. The LuCaP models have been extensively characterized by light microscopy, immunohistochemistry, expression arrays, RNASeq, IHC, exome sequencing and other methodologies. We have also determined responses of these PDXs to castration and docetaxel. To address the need for models representing the current tumor phenotypes that exist in patients who develop resistance to secondary androgen-targeting therapy, we have also evaluated responses to abiraterone and enzalutamide, and are experimentally developing abiraterone- and enzalutamide-resistant LuCaP PDXs. In addition, we are continuing to generate novel PDXs using abiraterone- and enzalutamide-resistant patient samples, and have four models that were established from abiraterone-resistant tumors. In summary, we have established a large biorepository of mCRPC specimens and PDXs. Moreover, due to the constant evolution of the advanced PCa phenotype we continue to acquire mCRPC specimens and establish novel PDXs that are refractory to the most recent treatments which allow us to investigate biology of late stage mCRPC and to provide valuable clinical specimens and LuCaP PDXs to the PCa research community. Citation Format: Colm Morrissey, Ming H. Lam, Tia S. Higano, Lawrence D. True, Martine Roudier, Robert B. Montgomery, Peter S. Nelson, Paul H. Lange, Evan Y. Yu, Robert L. Vessella, Eva Corey. The importance of clinically relevant rapid autopsy specimens and LuCaP patient-derived xenograft models to interrogate the heterogeneous and evolving treatment resistance of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1718. doi:10.1158/1538-7445.AM2015-1718