Androgen deprivation remains the standard therapy for patients with advanced prostate cancer (CAP) and causes disease remission in most men. However, CaP eventually recurs and thereafter the median survival of patients is less than 1 year. Thus, the transition from androgen-stimulated to recurrent growth represents a critical juncture in the progression of CaP. The Program Project's unifying hypothesis is that activation of the androgen receptor (AR) by low level androgens, mitogen signaling and coactivators mediates recurrent growth of CaP during androgen deprivation therapy. In the first three years of this P01, we demonstrated that AR is wild-type in most recurrent CaP, AR protein is expressed at similar levels in benign prostate and recurrent CaP, AR in recurrent CaP is hypersensitive (transactivated by femtomolar DHT and mitogens), tissue levels of testosterone and DHT within recurrent CaP appear sufficient for AR activation, stem-like cells within the prostate have neuroendocrine characteristics and the neovasculature of CaP xenografts is human not mouse in origin and appear androgen-responsive. The renewal consists of 3 closely-related projects. Project 1 will test the hypothesis that recurrence of CaP during androgen deprivation therapy can be prevented or delayed by attack upon tissue androgens and/or the androgen receptor. The mechanism of generation of tissue levels of androgens in recurrent CaP cells will be elucidated using CaP cell lines, CaP xenografts and clinical specimens. The accumulation of androgens in recurrent CaP tissue will be prevented by inhibiting their formation and augmenting their degradation. The androgen receptor will be inactivated using AR-dominant negatives and siRNA delivered using the lentiviral vector system. Project 2 will test the hypothesis that AR reactivation in the presence of low androgen levels is driven by mitogen signaling. Mechanisms by which EGF and heregulin enhance AR transcriptional activity in recurrent CaP will be determined with a particular emphasis upon AR phosphorylation, p160 coactivators and downstream signaling. The AR domains involved in EGF, heregulin and AR coactivator and corepressor regulation will be defined and the mechanism for loss of inhibition by AR antagonists elucidated. Novel coregulators that may have a role in AR transactivation will be tested for their potential as therapeutic targets. Project 3 will test the hypothesis that CaP recurrence originates from primitive, pluri-potential stem-like cells within the prostate. The role of the basal cell, vascular endothelium and neuroendocrine cells in the emergence of a population of CaP cells capable of growth in relative androgen absence will be examined in short-term human xenografts of benign prostate and CaP, the TRAMP and CWR22 models, and serial prostate biopsies obtained prior to and during androgen deprivation therapy.
Showing the most recent 10 out of 103 publications
