There is evidence both that activation of the vitamin D receptor (VDR) is beneficial in reducing the risk of prostate cancer and that VDR agonists are potential therapeutic agents in the treatment of prostate cancer. Although there are numerous studies showing that VDR agonists inhibit prostate cancer cell growth, the VDR targets that produce this response are, for the most part, unknown. Whether the changes observed in cancer cell lines will also occur in prostate tumors has not been addressed. Moreover, other than a demonstration that the growth of normal primary prostatic epithelial cells is also inhibited by VDR agonists (), little is known regarding the role of VDR in normal prostate. A better understanding of VDR action in normal and malignant prostate cells is critical to evaluating VDR agonists as potential chemopreventive and chemotherapeutic agents. Thus, we propose to identify the changes induced by activation of VDR in normal prostate and in tumor cells and to determine which of the changes are critical for the growth regulatory actions. To accomplish these goals, we will:
Specific Aim 1 : To identify genes regulated by VDR agonists in both LNCaP and LAPC-4 prostate cancer cells and to determine whether these genes are also regulated in tumors.
Specific Aim 2 : To elucidate the actions of VDR agonists in normal prostate epithelial and stromal cells.
Specific Aim 3 : Using a novel prostate disc organ culture model (PDOC), to determine whether the changes identified in cell culture are recapitulated in human tissues. One of the major limitations in translating findings from cell culture and animal models to human studies is the complexity and expense of a clinical trial. We propose a novel method to test the response of human prostate tumors as well as normal prostate tissue to VDR agonists that, if successful, will not only provide information regarding the utility of VDR agonists, but will establish a new paradigm for testing the effects of small molecules on human tumors prior to embarking on a clinical trial.
Specific Aim 4 : To assess the contribution of candidate regulated genes identified in aims 1-3, to the response to VDR agonist. Successful completion of these aims will not only lead to an understanding of how VDR agonists can contribute to reducing prostate incidence and aid in treatment, but may also allow us to develop methods to predict which patients will respond to treatment.
| Washington, Michele N; Kim, Jung-Sun; Weigel, Nancy L (2011) 1?,25-dihydroxyvitamin D3 inhibits C4-2 prostate cancer cell growth via a retinoblastoma protein (Rb)-independent G1 arrest. Prostate 71:98-110 |
| Washington, Michele N; Weigel, Nancy L (2010) 1{alpha},25-Dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. Endocrinology 151:1409-17 |
| Rohan, JoyAnn N Phillips; Weigel, Nancy L (2009) 1Alpha,25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells. Endocrinology 150:2046-54 |
