Abstract
Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) 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 in vivo and in vitro models of AR/ER+ breast cancer.Experimental Design: A series of in vitro 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+ breast cancer xenograft models.Results: 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+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ 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.Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1 It inhibits the growth of multiple AR/ER+ 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+ breast cancer patients. Clin Cancer Res; 23(24); 7608-20. ©2017 AACR.
Highlights
Breast cancer is the second leading cause of cancer-related death in women, with an estimated 246,660 newly diagnosed cases and 40,450 deaths in the United States alone in 2016 [1]
No appreciable interaction of RAD140 with any targets screened, other than androgen receptor (AR) and progesterone receptor (PR), was detected. These results indicate RAD140 binds to AR with high affinity and specificity
This study demonstrates for the first time that RAD140, an orally available selective AR modulator (SARM), is an AR agonist in breast cancer cells and suppresses the growth and proliferation of multiple AR/ERþ breast cancer cell line and xenograft models
Summary
Breast cancer is the second leading cause of cancer-related death in women, with an estimated 246,660 newly diagnosed cases and 40,450 deaths in the United States alone in 2016 [1]. Breast cancer is a heterogeneous disease categorized into several histopathologic subtypes based on the status of estrogen receptor a (ER), progesterone receptor (PR), and HER2 receptor. ERpositive (ERþ) breast cancers are treated with standard-ofcare agents targeting the ER axis, including tamoxifen, fulvestrant, and aromatase inhibitors (AI), and HER2-positive tumors are treated with HER2 inhibitors, such as trastuzumab, novel therapeutic approaches are still needed to address resistance emerging from these established regimens [2, 3]. Combined administration of ER-targeted therapies with the inhibitors of cyclin-dependent kinase (CDK) 4/6 [4] or mTOR [5] have yielded improved therapeutic efficacy in ERþ breast cancer, and these. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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