Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR41-Sex Hormone Receptors in Development, Aging and Cancer: Omics Approaches
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 121 (Moscone Center)
Minyoung Lim, Maya Otto-Duessel, Leila Su, Miaoling He and Jeremy Jones*
City of Hope, Duarte, CA
Most metastatic prostate cancers (PC), even castration-resistant PC, remain dependent upon androgen receptor (AR) signaling for growth. Resistance to novel PC drugs like abiraterone and enzalutamide appears to occur through ligand-independent AR signaling, often by expression of AR splice variants that lack the ligand binding domain (LBD). Thus, drugs that inhibit AR activity via domains other than the LBD may provide a way to inhibit the growth of ligand-independent, AR-driven PC. We recently reported the discovery of the first non-competitive, ligand-independent AR inhibitor, pyrvinium pamoate (PP). This drug was discovered from a screen for inhibitors of AR conformation change and inhibits endogenous AR activity with 12nM potency and functions synergistically with competitive antagonists. It does not compete for ligand binding nor does it inhibit AR nuclear accumulation, but it does prevent the recruitment of RNA polymerase II to transcription start sites. Here, we use a novel method of target identification to demonstrate that AR is a direct target of PP in PC cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Computational modeling predicts that PP binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants. PP also inhibits androgen-independent AR activation by HER2 kinase. The anti-androgen activity of PP manifests in the ability to inhibit the castration-resistant growth of PC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs), but not structurally unrelated transcription factors.  PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density, but does not affect lean body mass. Our results suggest that the non-competitive AR inhibitor PP has significant potential to treat metastatic PC, including cancers driven by ligand-independent AR signaling.

Nothing to Disclose: ML, MO, LS, MH, JJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by NIH K99/R00 CA138711 to JOJ.
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