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 "castration." The effect of castration upon the androgen axis will be assessed on 4 levels in vitro and 6 levels in vivo. The 4 levels of assessment in vitro and in vivo will include 1) changes in androgen metabolism enzymes at the mRNA level using qRT-PCR and protein level using immunohistochemistry (IHC);2) androgen levels using LC-MS;3) androgen-regulated gene expression using IHC for PSA, NkxS.1 and hK2;and 4) cell growth. Measures in vivo will include 5) time to progression and 6) survival. Androgen metabolism after ADT will be studied using androgen-sensitive CWR22 cell suspensions, the androgen-dependent CWR22 xenograft and a fresh surgical tissue xenograft model. Changes in androgen metabolism critical for survival after ADT will be targeted using shRNA or drug in vitro and lentiviral shRNA and/or drug in vivo (Aim 1). Testicular androgens formed by intracrine metabolism of adrenal androgens will be removed using 53-reductase or Sult2A1 delivered using lentiviral infection (Aim 2). Finally, AR will be removed using lentiviral AR shRNA constructs or AR degrading small molecules (Aim 3).
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.
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