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ASCO GU 2008 - Androgen Receptor Reactivation After Androgen Deprivation Therapy - Highlight

UroToday.com - Dr. Balk discussed the modest clinical benefit of AR antagonists in addition to androgen-deprivation therapy (ADT). However, AR is expressed at levels that are comparable to primary CaP, although the expression may not be heterogeneous. It is possible that there is cell cycle regulation to AR expression. He pointed out that progression to castration resistant CaP is associated with substantial reactivation of AR transcriptional activity. AR regulated TMPRSS2-ERG gene fusion transcripts are expressed in castration resistant CaP (about 2.7 fold). Thus, AR appears critical for tumor growth in castration resistant CaP. This is supported by laboratory data that AR downregulation in castration resistant CaP cells and xenografts suppresses cell growth.. Two mechanisms may account for this; AR expression is increased or AR mutation occurs. AR mRNA is increased >5-fold in castration resistant CaP, but AR protein is not markedly increased and it is not clear that this can restore AR activity after castration. AR mutations occur primarily in patients treated long-term with AR antagonists and can convert these drugs into agonists, but AR remains wild-type in most patients. He showed data from several groups that CaP adapts to castration by increased intracellular androgen uptake and/or synthesis. The high intracellular testosterone levels may account for resistance to AR antagonists.

Dr. Balk reviewed the normal prostate enzyme pathway for converting DHEA to androstenedione (HSD3B), androstenedione to testosterone, and testosterone to DHT. In castration resistant CaP, transcripts for testosterone and DHT are increased, while SRD5A2 is reduced to 50%. This is consistent with high testosterone levels. The transcripts for enzymes that degrade DHT are also increased in castration resistant CaP perhaps reflecting a feedback loop. Ketoconazole and abiraterone inhibit CYP17A1 early in the synthesis pathway, and have 50% response rates. Abiraterone reduces DHEA only 3-fold, thus perhaps still leaving substrate for synthesis.

In addition to the above mechanisms, CaP xenografts that relapse in castrated mice are hypersensitive to low levels of androgen. This may be due to increased expression of transcriptional coactivator proteins, increased EGF receptor which enhances phosphorylation, AR co-stimulatory activity of transcriptional factors, increased Ras activated kinase pathways and tyrosine phosphorylation. Thus CaP cells adapt to castration by a variety of mechanisms including AR expression and mutations, increased intracrine androgens, increased sensitivity to androgens and altered kinase pathways. This lays the basis for developing more potent androgen antagonists.

Presented by Steven Balk, MD, PhD at the American Society of Clinical Oncology (ASCO) - 2008 Genitourinary Cancers Symposium - A Multidisciplinary Approach - February 14-16, 2008 San Francisco, California, USA

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS Professor & Chairman Department of Urology University of California, Davis, School of Medicine Sacramento, CA

UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice.

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ASCO gu 2008 - Androgen receptorilor de reactivare dupã Androgen privarea terapie - Evidenþiaþi - ASCO GU 2008 - Androgen Receptor Reactivation After Androgen Deprivation Therapy - Highlight - articole medicale engleza - startsanatate