Abstract A3: A tumorgraft model of castration-resistant primary prostate cancer

Abstract

Abstract Androgen receptor (AR) signaling plays a central role in all stages of prostate cancer (PCa). Androgen deprivation therapy (ADT) is used as adjuvant therapy for high-risk PCa as well as the first-line therapy for metastatic PCa. However, tumor remissions are temporary and patients almost inevitably progress to become castration resistant prostate cancer (CRPC). Most CRPC still expresses AR and depends on AR for growth, therefore, there is an urgent need to understand the regulation of AR expression and to find novel ways of inhibiting this pathway in CRPC. We developed a novel realistic model for primary CRPC by establishing tumorgrafts with thin, precision-cut tissue slices derived from high-grade primary PCa under the renal capsule of immunodeficient mice supplemented with subcutaneous testosterone pellets. One month after the implantation, the testosterones pellets were removed and the mice were castrated. Tumorgrafts from control and castrated mice were harvested one month after castration and fixed in formalin. Immunohistochemistry was performed to examine the expression of genes of interest in the grafts. Tumorgrafts derived from high-grade primary PCa resemble the original tumors in expression of all genes examined. Specifically, they are positive for AR, prostate specific antigen (PSA), cytokeratin 18, and AMCAR, but negative for p63. After castration, cancer cells remained in grafts derived from two of four tumors, whereas cancer cells in grafts derived from the other two tumors were almost completely eliminated, suggesting that some tumors respond to androgen deprivation therapy (ADT) better than the others. In the castration-resistant tumorgrafts (CRTs), PSA expression was diminished in cancer cells, but AR and cytokeratin 18 expression remained, similar to responses of human prostate to ADT. In addition, cancer cells in CRTs were less proliferative than in control grafts as determined by Ki67 staining consistent with the observation that ADT inhibit cell proliferation in human prostate. More importantly, CRTs expressed AR target genes that have been reported to be upregulated under androgen ablation in other experimental models. For example, the number of cyclin A-expressing cells was significantly higher in CRTs than in control grafts. Our results demonstrated that our novel CRT model has the appropriate characteristics to serve as a useful tool to model primary CRPC. Our results demonstrated that our novel CRT model has the appropriate characteristics to serve as a useful tool to model primary CRPC and may be used as a surrogate model for clinical trials to achieve rapid and less expressive screening of therapeutic agents for neoadjuvant or adjuvant therapy of PCa. Citation Format: Hongjuan Zhao, Alan Thong, Rosie Nolley, Stephen Reese, Jennifer Santos, Donna Peehl. A tumorgraft model of castrationresistant primary prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A3.