Castration Adapted Prostate Cancer: Androgen Metabolic Pathways In Recurrent Disease
December 10, 2017
UroToday - Dr. Peter Nelson, University of Washington presented "Castration Adapted Prostate Cancer: Androgen Metabolic Pathways in Recurrent Disease" in the session "New Ideas in Prostate Cancer Recurrence after Castration".
Dr. Nelson pointed out that between 2-10 years following androgen-deprivation therapy (ADT) androgen-independent (AICaP) clones will develop. This is partially due to mechanisms independent of androgens, with up to 5 pathways identified. These concepts work under the presumption that androgen levels have been adequately suppressed. However, clinically the meta-analysis of combined androgen blockade does demonstrate a small survival benefit using an anti-androgen.
He discussed that residual prostate androgens remain after a variety of endocrine manipulations. A GnRH antagonist given to patients resulted in a castrate level in 24 hours and greater reductions of testosterone and DHT in prostate tissue. This response is heterogeneous among individuals at the gene and protein levels. Analysis of neoadjuvant ADT radical prostatectomy tissue demonstrated that most genes examined are still active at the transcript and protein levels after 3-6 months of ADT. Using tissue from the rapid autopsy program, patients with untreated CaP have levels above the castrate level, but a significant number of metastatic castrate-treated patients do as well.
Xenografts grown in intact or castrate mice demonstrate that both have detectable androgen levels in the tumor tissue, despite the fact that rodents do not have significant adrenal androgen production. These tumors represent "castrate-adapted" CaP. In these tumors, transcripts for all the steroid molecules involved in the androgen synthesis pathway are still present. Numerous drugs are in development that targets the intracrine androgen pathways.
From the SUO/SBUR Joint Meeting - Saturday, May 19, 2007 - AUA Annual Meeting, Anaheim, CA
Reported by UroToday Contributing Editor Christopher P. Evans, MD, FACS
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