Abstract
<div>Abstract<p><b>Purpose:</b> Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER<sup>+</sup>) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in <i>in vivo</i> and <i>in vitro</i> models of AR/ER<sup>+</sup> breast cancer.</p><p><b>Experimental Design:</b> A series of <i>in vitro</i> assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER<sup>+</sup> breast cancer xenograft models.</p><p><b>Results:</b> RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER<sup>+</sup> breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the <i>ESR1</i> gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER<sup>+</sup> PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib.</p><p><b>Conclusions:</b> RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of <i>ESR1</i>. It inhibits the growth of multiple AR/ER<sup>+</sup> breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER<sup>+</sup> breast cancer patients. <i>Clin Cancer Res; 23(24); 7608–20. ©2017 AACR</i>.</p></div>
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