Selective AR Modulators that Distinguish Proliferative from Differentiative Gene Promoters
Annual rept. 30 Jul 2014-29 Jul 2015
MICHIGAN UNIV ANN ARBOR
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Androgen signaling via its receptor, AR, remains the key therapeutic target in prostate cancer. Despite advances in treatment, disease ultimately recurs. Our goal is to inhibit AR target genes that drive cancer growth but retain expression of those for normal cell differentiation. Our hypothesis is that these sets of genes differ in androgen response elements AREs, with genes driving proliferation relying on consensus inverted repeats cARE and genes promoting differentiation relying on selective direct repeats or half-sites sAREs. Compounds interacting with any AR domain, or interacting molecules, may alter AR conformation to affect response element recognition. To identify such compounds, we developed a high-throughput screen for differential AR action with transfected fluorescent reporters driven by multimerized cAREs or sAREs. Over 10,000 compounds from several libraries, including 2,000 FDA-approved drugs, were tested in multiple screens. The two best hits were confirmed in rescreens and validated for differential effects on AR activity in vitro and in vivo. In particular, these compounds differentially affect AR-dependent gene expression in LNCaP cells. We are currently pursuing the basis for a difference in AR binding to DNA and within chromatin, and will test differential effects in mouse cancer models.
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