The Androgen Receptor in Hormone Refractory Disease

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The vast majority of prostate cancers are androgen dependent, and androgen deprivation therapy (ADT) remains the standard treatment for non-organ-confined prostate cancer. Unfortunately, patients treated with ADT invariably relapse with progressive systemic prostate cancer that has been termed hormone-refractory or androgen-independent prostate cancer (AlCaP). Significantly, most cases of AlCaP are associated with high levels of androgen receptor (AR) mRNA and protein, as well as renewed expression of androgen regulated genes (such as prostate specific antigen (PSA), TMPRSS2, and the recently identified TMPRSS2/ETS fusion genes), suggesting that AR and AR-regulated genes remain critical for tumor growth in AlCaP. However, the molecular events mediating the apparent reactivation of AR transcriptional activity in AlCaP, and the critical downstream AR-regulated genes, remain to be determined. We recently reported our results using Affymetrix oligonucleotide microarrays to compare gene expression in a series of laser capture microdissected primary prostate cancer samples versus AlCaP bone marrow metastases. These studies demonstrated a high level of expression of AR mRNA in AlCaP together with renewed expression of multiple strongly AR-regulated genes, confirming substantial reactivation of AR-mediated transcription despite castrate androgen levels. With respect to potential mechanisms for this AR reactivation, we found that AlCaP samples had marked increases in enzymes that mediate androgen metabolism, suggesting that enhanced synthesis of the ligands testosterone and dihydrotestosterone (DHT) by AlCaP is one potential mechanism contributing to relapse after castration. The Specific Aims of this Project are to: Aim 1: Complete the current trial of ketoconozole, hydrocortisone, and dutasteride, and initiate new phase II clinical trials of compounds that suppress AR expression or function in androgen-independent Prostate cancer. Aim 2: Combine gene expression data from androgen-independent prostate cancer cell lines and xenografts with AR ChlP-on-chip from these cell lines to identify critical AR cooperating factors and regulated genes that may be therapeutic targets in androgen independent prostate cancer. Aim 3: Validate AR-regulated genes as therapeutic targets in clinical AlCaP cancer.