Abstract 2780: Xenografts of human prostate cancer - a genetic profile analysis.
Authors: Palanisamy Nallasivam , Yang Jun , Wan Xinhai , Araujo John C. , Efstathiou Eleni , Pisters Louis , Bhalla Ritu , Tomlins Scott , Kunju Lakshmi P. , Chinnaiyan Arul , Logothetis Christopher J. , Troncoso Patricia , Navone Nora M. 
Published: August 2014

Prostate cancer (PCa) is the second leading cause of cancer-related death in the US. Recent clinical trials have shown responses in a subpopulation of patients; thus we need methods to identify likely responders. The genetic basis of PCa is understood to the extent that patients can be classified based on underlying molecular aberrations: 50-60% of PCas have rearrangements in ERG, ETV1, ETV4, ETV5, BRAF, and RAF1 and overexpression of SPINK1 and AR. PCas with PTEN deletion along with ERG have altered clinical behavior. We developed a strategy to establish PCa xenografts with tissue taken directly from men and implanted subcutaneously in SCID mice. After its growth, the tumor is harvested and sequentially passaged over 4 or 5 mice. We have established 62 PCa xenografts since the program's inception. These xenografts, which are often developed while the donor PCa patient is alive, have proven valuable for testing drugs and have led to initiation of a promising clinical study (ClinicalTrials.gov: NCT00831792). In the study reported here we systematically characterized 51/62 xenografts for the presence of known PCa markers by immunohistochemistry and fluorescence in situ hybridization. The PCa xenografts were derived from PCas in the prostate or direct extensions to adjacent organs (21) or from metastases to bone (4), lymph node (3), liver (6), thyroid (1), testis (1), adrenal gland (2), brain (3), and unusual sites (skin, chest wall, soft tissue) (4) or ascites (3), and pleural effusions (3). 81% of xenografts derived from prostatic adenocarcinomas were AR positive (27/33); 16 were small-cell, poorly differentiated neuroendocrine carcinomas or ductal adenocarcinomas and did not express AR. One sarcomatoid and 1 ductal adenocarcinoma expressed AR; 77% of evaluable tumors had a deletion in PTEN (31/40); 48% of AR-positive tumors expressed recurrent gene fusions (eg, ERG, ETV1, ETV5) (13/27). Together, these results in this cohort_AR and recurrent gene fusion expression and PTEN deletion_nicely correlate with findings in human PCa. We next assessed whether PCa xenografts maintained histopathologic and molecular fidelity with the human tumor of origin in selected cases (n=16). Histopathologic pattern and recurrent gene fusion expression were the same in the paired human and mouse tissue. The AR and PTEN status were the same in most paired human and mouse samples. In 4 cases, AR expression was lost or PTEN deleted in the PCa xenograft, suggesting that selection for more aggressive genotypes may occur during xenograft development and that PCa xenografts develop by selecting cells’ drivers of cancer progression. In conclusion, we have developed a protocol for xenograft development that has fidelity with human PCa. This approach has provided a repository of clinically annotated samples that can be linked prospectively to clinical progression/response to therapy and thus will help identify therapy responders.

Citation Format: Nallasivam Palanisamy, Jun Yang, Xinhai Wan, John C. Araujo, Eleni Efstathiou, Louis Pisters, Ritu Bhalla, Scott Tomlins, Lakshmi P. Kunju, Arul Chinnaiyan, Christopher J. Logothetis, Patricia Troncoso, Nora M. Navone. Xenografts of human prostate cancer - a genetic profile analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2780. doi:10.1158/1538-7445.AM2013-2780