UroToday - Dr. Mark Rubin, Boston, USA spoke on "The Role of Androgens in Prostate Cancer Development: New Insights" at the plenary session of the EAU on Friday March 23, 2007. Dr. Rubin is a uropathologist and presented data that connect new molecular paradigms to novel clinical treatments.

The androgen receptor (AR) and its role in the prostate cell were reviewed. Androgens are essential for the development and maintenance of the prostate gland. He stated that metastatic CaP deaths remains grim and has not changed much in the past 30 years. Mechanisms of androgen-independence (AI) include; AR amplification, AR mutations (we do not completely understand the role of mutations well at this point), ligand-independent activation (signaling through other pathways such as Her-2 neu, provides new therapies), co-activators (new therapies such as targeting heat shock proteins) and other mechanisms such as bypass pathways involved in apoptosis and lurker-cell pathways that would implicate stem cells, etc.

If AR is the best target, why are new therapies not working better, he asked? Dr. Rubin presented data from Dr. Sawyers, showing that AR is upregulated in AICAP. Transfection and expression of AR into prostate cancer cell lines initiated quicker growth that responded poorer to anti-androgens. They also regrew faster after castration in mice. Mutations in AR that resulted in loss of its ability to translocate to the nucleus decreased its functional potential. Also, increased AR expression converts antagonists to agonists, such as flutamide being able to facilitate tumor cell proliferation. Genes associated with cancer progression can be upregulated by AR with either anti-androgens or androgens. Regarding bypass pathways, alterations in gene expression also facilitate cancer progression. Identification of these pathways can provide the basis for new clinical targets.

He discussed chemical genomic prediction of AR repressors that identified a 27 gene signature that profiles tumor behavior. One can then assess compounds that alter this specific signature, suggesting potential clinical efficacy. Celastrol is a novel compound that was tested in this gene expression signature model both with and without the presence of androgens. Differences were found in these different androgen states. Celastrol was shown to down-regulated HSP-90 and decrease the expression of AR and other downstream genes.

He discussed gene fusion of the ETS protein and TMPRSS2. The vast majority of prostate cancers have gene fusions. Hormonal treatment responses can be assessed in this setting. This sets the stage for targeting either the ETS transcription factor or the fusion product for therapeutic intervention.

Reviewed by UroToday Contributing Editor By Christopher P. Evans, M.D., FACS

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