Androgen Metabolism in Progression to Androgen-Independent Prostate Cancer
Abstract
The majority of prostate cancers (PCa) are androgen dependent, and androgen deprivation therapy (ADT) remains as the standard treatment for non-organ confined disease. Unfortunately, patients treated with ADT invariably relapse with rapidly progressive systemic PCa, which has been termed hormone refractory, androgen independent, or castration resistant prostate cancer (CRPC). Significantly, the androgen receptor (AR) is highly expressed in most cases of CRPC and appears to be transcriptionally active, but the molecular events mediating the progression to CRPC and apparent reactivation of AR transcriptional activity remain to be defined. Our previous data indicate that increased intratumoral production of testosterone from precursors (adrenal androgens and possibly endogenous sterols) contributes to the reactivation of AR transcriptional activity in CRPC. We proposed that tumors adapt to androgen deprivation therapy by increasing their synthesis of potent androgens from available weak adrenal androgens (and possibly from endogenous precursors), and that AKR1C3 is a key enzyme in this process. Our objectives were to test these hypotheses using cell line and xenograft models (Aim 1) and by measuring androgen and androgen metabolite levels in patients who progress to CRPC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2011
- Accession Number
- ADA547188
Entities
People
- Steven P Balk
Organizations
- Beth Israel Deaconess Medical Center