Project 1 has contributed to two paradigm changing discoveries. First, the androgen receptor (AR) pathway appears critical to the growth of castration-recurrent prostate cancer (CaP) in spite of castrate levels of circulating testicular androgens. Second, castration-recurrent CaP produces high tissue levels of testosterone (T) and dihydrotestosterone (DHT), the preferred AR ligand. Intracrine-produced testicular androgens present a target for novel therapies. Further advances may result from applying novel treatments to CaP coincidental with androgen deprivation therapy (ADT) when CaP cell death is at a maximum and surviving cells are under greatest stress. The central hypothesis of the proposed studies is that CaP can be cured or remission extended by a coordinated attack upon intracrine androgen metabolism and AR coincidental with elimination of circulating testicular androgens (medical or surgical castration). In order to test this hypothesis and allow the formulation of an appropriate clinical trial in advanced CaP, the response to ADT will be assessed using preclinical models in the immediate post-castration period. In general, cell or tissue sampling will be conducted just prior to castration and 12h and 1, 2, 4, 8, 16 and 30d after

Public Health Relevance

Much has been learned about CaP that recurs during ADT but an American still dies from CaP every 18 minutes. The proposed studies seek to understand better how CaP adjusts acutely to ADT so that some CaP cells survive to provide a reservoir for later growth to kill the patient. New therapies directed against the changes in androgen metabolism or the AR that allow these CaP cells to survive may extend remission due to ADT or even cure CaP.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077739-14
Application #
8470587
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$196,510
Indirect Cost
$13,855
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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