Abstract 3281: Development of a novel transgenic mouse model for prostate cancer

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in American men. Androgen-deprivation therapy (ADT) is a common and effective therapy for advanced / metastatic PCa. However, most initially regressed PCa will relapse and become castration-resistant PCa (CRPC). Currently, there is no cure for CRPC. Chemotherapy, including agents such as Docetaxel, is a standard therapy for CRPC. However, it only modestly extends patient survival. Therefore, castration resistance and chemoresistance of PCa are huge medical problems for PCa treatment. To overcome castration resistance and chemoresistance, it is crucial to delineate the underlying molecular mechanisms. c-Myc is the most significantly amplified oncogene in human PCa, and its overexpression is very common in PCa as early as prostatic intraepithelial neoplasia (PIN). These indicate its critical roles in PCa progression and the development of therapy-resistance. Transgenic models are widely used in cancer research. Accordingly, Hi-MYC transgenic model has been created using an enhanced probasin promoter to drive c-Myc overexpression in prostate epithelia. These mice develop invasive prostate carcinomas that share molecular features with human PCa. However, since the probasin promoter activity is androgen-dependent, these MYC prostate tumors lose c-Myc oncogene expression upon castration. As a result, the tumor regression in these androgen-depleted Hi-MYC mice represents the mixed effects of both an artificial direct effect from loss of oncogene expression and a potential real effect from tumor cellular responses to androgen-ablation that are relevant to human PCa. Finally, Hi-MYC mice do not develop CRPC tumors after castration. Therefore, the Hi-MYC model, along with other similarly created Myc-based transgenic models for PCa, cannot be used to study CRPC, the lethal form of PCa. To study CRPC and chemoresistance of CRPC, we have developed a novel transgenic model (CAG-SMIL) for human PCa. This model allows us to specifically turn on c-Myc oncogene expression in prostate epithelia after crossing CAG-SMIL mice with PB-Cre4 mice. In addition, once turned on, the expression of c-Myc transgene will be driven by an enhanced beta-actin promoter that is androgen-independent. Therefore, after castration of the prostate tumor bearing PB-Cre4/CAG-SMIL males, we will be able to, for the first time, concisely study c-Myc signaling pathway 1) in castration induced prostate tumor regression, 2) in the recurrence of CRPC tumors, and 3) in the development of chemoresistance in CRPC tumors. Finally, we have incorporated an enhanced luciferase reporter into our transgenic model. This will allow a real-time in vivo bioluminescence imaging (BLI imaging) for prostate tumor progression, tumor response to various therapeutic agents, as well as tumor relapse after the development of therapy (castration and chemotherapy) resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3281. doi:1538-7445.AM2012-3281