AR antagonists including bicalutamide and enzalutamide have been shown to reduce the growth of AR-positive but ER −, including triple-negative, breast cancer in preclinical models ( 12–14) and in patients ( 11). Although AR is widely present in breast cancer tissue, accumulating evidence has demonstrated that the role of AR in these tumors is subtype dependent ( 8–11). Recent histopathologic studies revealed that the androgen receptor (AR) is the most commonly expressed hormone receptor in breast cancer, with 75% to 90% of ER + and approximately 30% of ER − breast cancers expressing AR ( 6, 7). More recently, 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 ER + breast cancer, and these combination therapies now represent a new generation of standard of care for this indication. Although ER-positive (ER +) breast cancers are now treated with standard-of-care 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). Breast cancer is a heterogeneous disease categorized into several histopathologic subtypes based on the status of estrogen receptor α (ER), progesterone receptor (PR), and HER2 receptor. Introductionīreast 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). The first-in-human study of RAD140 in recurrent breast cancer has been initiated. RAD140 may present a novel therapeutic approach for AR/ER + breast cancer.
These suggest a distinct AR-mediated mechanism of action compared with the traditional ER-targeted agents. Mechanistically, RAD140 potently regulates AR target genes, while suppressing the ER targets and the ESR1 mRNA. The coadministration of RAD140 with CDK4/6 inhibitor elicited enhanced efficacy in these AR/ER + models. We report here that RAD140, an oral, tissue selective androgen receptor modulator, exhibited potent activity in inhibiting the growth of multiple AR/ER + breast cancer xenograft models. However, the clinical utility of the classic steroidal androgen-based therapies has been limited. Androgens inhibit the proliferation of AR and ER-positive (AR/ER +) breast cancer cells, and androgen-based treatment showed clinical benefit in breast cancer patients. The expression of the androgen receptor (AR) in estrogen receptor (ER)–positive breast cancer has been well described. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER + breast cancer patients. It inhibits the growth of multiple AR/ER + breast cancer PDX models as a single agent, and in combination with palbociclib. 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.Ĭonclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER + PDX models. Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment.
Oral administration of RAD140 substantially inhibited the growth of AR/ER + breast cancer patient-derived xenografts (PDX). Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER + breast cancer xenograft models.
#RAD 140 RESULTS SERIES#
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.Įxperimental 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. 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.
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