AH 7614 Breast Cancer Although androgens have

Breast Cancer: Although androgens have been considered to be a risk factor in prostate cancer they have been recommended to treat breast cancers. Even before the discovery of SERMs and aromatase inhibitors, steroidal androgens such as medroxyprogesterone and fluoxymesterone were used to treat breast cancer (Coss et al., 2014). Expression of the AR in breast cancer has been consistently correlated with better disease-free- and overall-survival (Sultana et al., 2014). In addition, combined expression of the AR with steroidogenic AH 7614 that result in increased synthesis of androgens have been shown to be extremely beneficial in breast cancer (McNamara et al., 2013). However, these steroidal androgens, as indicated above, caused virilization, resulting in their discontinuation. With the discovery of SARMs, women with breast cancer may have another safe and effective treatment option. Although the mechanism underlying the role of the AR in breast cancer is not completely understood, experimental evidence suggests that the AR inhibits ER function to inhibit the growth of ER-positive breast cancers (Peters et al., 2009). While the mechanism of action in ER-positive breast cancer is somewhat clearer, the mechanism of action in ER-negative or triple negative breast cancer (TNBC) is complex and has not been elucidated. Both a SARM, enobosarm, and an antagonist, enzalutamide, are in clinical trials to treat breast cancers. Recent press release from GTx, Inc., which is currently conducting a clinical trial with enobosarm in women with ER-positive breast cancer, indicated that the SARM slowed further growth of cancer (partial response and stable disease) in a subset of patients (GTx Reports Results, 2016). Although no clinical data have been published on enzalutamide in ER-positive breast cancer, a phase I clinical trial to evaluate safety and bioavailability of enzalutamide in women with ER-positive breast cancer showed that enzalutamide reduced the serum concentration of anastrozole and exemestane by 90% and 50%, respectively, which could impact the efficacy of the aromatase inhibitors (Schwartzberg et al., 2017). However, enzalutamide has shown early promise in triple-negative breast cancer (TNBC). With TNBC being further sub-classified into several subsets, Multimeric protein may be possible that a SARM and an antagonist might provide anti-proliferative effects to distinct subsets of TNBC (Lehmann et al., 2011). This concept will be evaluated in future clinical trials. The reader is referred to a recent review for detailed information on the potential role of AR in breast cancer (Narayanan and Dalton, 2016). Current clinical development paradigm of SARMs: Currently, to the best of our knowledge, the only SARM that is in clinical trials is enobosarm (GTx, Inc., Memphis, TN). Other companies that have previously pursued SARMs clinically are Ligand Pharmaceuticals, Merck, Glaxo, and Radius, Inc. A search of the clinicaltrials.gov database returned a small number of trials, many of which are phase I studies and investigator-initiated exploratory trials. While several other SARMs have been tested clinically for various diseases, they have not advanced beyond phase II proof-of-concept. Enobosarm was tested in two double-blind placebo-controlled phase III clinical trials in lung cancer patients at risk for cachexia. While enobosarm significantly improved muscle mass in both the trials, it only marginally increased the physical function. Similarly, two phase III trials with anamorelin, a non-peptide, orally-active, centrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor, in subjects with lung cancer and cachexia showed that it increased muscle mass but failed to improve hand grip strength (Temel et al., 2016). The European Medicines Agency (EMA) recent refusal of the marketing authorization for anamorelin on the basis of its “marginal effect … on lean body mass and no proven effect on hand grip strength or quality of life” casts further doubt on the path forward for the use of such agents in muscle wasting associated with cancer. We speculate that the results of the phase III trials with enobosarm and anamorelin and the complexity in conducting clinical trials in this space have discouraged other companies from pursuing SARMs in cancer-associated muscle wasting and that the field is seeking regulatory clarity before proceeding (Fearon et al., 2015).