Abstract A03: Analyses of a prostate cancer patient-derived xenografts series, a resource for translational research

Abstract

Abstract Patients with metastatic prostate cancer (PCa) have effective therapy options, but none of them are curative. Thus, their mortality rates are persistently high. Essential to furthering our progress in PCa research and therapy development is a spectrum of models that reflect the heterogeneity of the disease at each tumor site as well as the different histological variants of PCa (e.g., adenocarcinoma, small cell carcinoma). To address this challenge, we developed a strategy to establish PCa patient-derived xenografts (PDXs), using PCa tissue specimens taken from PCa sites demonstrating clinical progression. This approach provided a diverse repository of PDXs that can be linked prospectively with clinical progression and led to the identification of clinically relevant therapy targets and have proven valuable for testing drugs. We studied the first 50 PDXs developed under our program to a) define the histopathological features of paired human PCa and corresponding PDXs applying the clinically defined morphological characterization groupings of human cancer to the PDX tumors; b) assess the expression of genes known to play roles in PCa pathogenesis (e.g., androgen receptor, PTEN, ETS gene fusions) in PDXs and the human tumors of origin using immunohistochemistry and fluorescence in situ hybridization and c) perform array comparative genomic hybridization to 42 PDXs. We found that the histopathological and molecular pattern of these PDXs maintain the fidelity with the human tumor of origin. Furthermore, of the 50 cases studied, 32 (64%) were adenocarcinomas, and 16 (32%) were small cell carcinomas, poorly differentiated neuroendocrine carcinomas or mixed adenocarcinoma/ small cell carcinomas. In our cohort, we also have one sarcomatoid tumor and one ductal adenocarcinoma. Of the 32 adenocarcinomas in this cohort, 26 were AR-positive (81%), and 11 of the 27 AR-positive adenocarcinomas (41%) had aberrant expression of genes frequently involved in recurrent rearrangement (e.g., ERG, ETV1, ETV5). Also, SCCs and poorly differentiated neuroendocrine carcinomas did not express AR and were negative for ERG. This distribution recapitulates that of human PCa in the general population. Comparative genomic hybridization demonstrated gains and losses previously reported in PCa with a defined cluster of genomic aberrations. Significant differences in oncogenic pathways activation in pairs of PDXs derived from different areas of the same tumor suggesting divergent cellular progression. Finally, using this platform, we identified a focal deletion of speckle-type POZ protein-like (SPOPL) gene in 7/28 PDX. SPOPL is a MATH-BTB protein that shares an overall 85% sequence identity with SPOP (a SPOPL paralog). SPOP was recently reported to be mutated in about 8% of PCa and to define a molecular subclass of PCa. No mutations were found in SPOP in our cohort. In support of our findings, deletions on SPOPL were also found in about 7% of the PCa in TCGA data suggesting that our cohort is a reliable platform for discovery. In conclusion, we have developed a dynamic repository of clinically annotated samples that can be used as a discovery platform. Furthermore, these clinically annotated samples can be linked prospectively to clinical progression/response to therapy and thus will help define therapeutic targets for subpopulations of men and to identify likely responders to previous and upcoming therapies. Citation Format: Nallasivam Palanisamy, Jun Yang, Xinhai Wan, Elsa M. li Ning Tapia, John C. Araujo, Eleni Efstathiou, Estefania Labanca, Louis Pisters, Ana Aparicio, Ritu Bhalla, Scott Tomlins, Lakshmi P. Kunju, Arul Chinnaiyan, Christopher J. Logothetis, Patricia Troncoso, Nora M. Navone. Analyses of a prostate cancer patient-derived xenografts series, a resource for translational research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A03.