Chemoprevention is an attractive approach to prostate cancer control. Several agents have been identified to be effective in reducing risk;among these are finasteride and selenium. In two independent phase III studies, treatment with finasteride or selenium decreased prostate cancer by 25% or 50%, respectively, although in the selenium trial, prostate cancer was not the primary endpoint. Finasteride is a competitive inhibitor of 5a-reductase, an enzyme responsible for the irreversible conversion of testosterone to dihydrotestosterone (DHT). Preliminary results from our laboratory showed that selenium depresses androgen receptor (AR)abundance, AR trans-activating activity and the expression of AR-regulated genes. Based on the above information, we propose to test the following hypotheses. Hypothesis #1: Since finasteride and selenium target different steps along the androgen signaling pathway, combining these two agents is likely to produce a cooperative or synergistic effect in prostate cancer prevention. Hypothesis #2: Disrupting the interaction between the DHT-AR complex with FOXO1A is critical for the anticancer effect of finasteride/selenium. FOXO1A is physically bound to and negatively regulated by DHT-AR. Through the mechanism of decreasing DHT by finasteride and AR availability by selenium, FOXO1A is expected to be liberated. As a transcription factor, FOXO1A induces the expression of a number of pro-apoptotic genes. The research plan consists of four specific aims.
Aim 1 : To determine (a) whether the combination of finasteride/selenium results in a further suppression of androgen signaling when compared to the single agent, and (b) whether finasteride has other effects on AR signaling beyond its known function of blocking 5a-reductase.
Aim 2 : To investigate the role of FOXO1A, a transcription factor negatively regulated by AR, in mediating the anticancer effect of finasteride and selenium.
Aim 3 : To study (a) the activation of initiator caspases and executioner caspases by finasteride or selenium, or both;and (b) whether restoration of AR signaling reverses the effect of each agent on caspase activation and caspase-mediated apoptosis.
Aim 4 : To validate the anticancer efficacy of finasteride/selenium and the accompanying molecular changes (information obtained from Aims 1to 3) in human prostate cancer xenograft models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA126804-05
Application #
8324491
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$335,598
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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