In prostate cancer the androgen receptor (AR) activates a lineage-specific, oncogenic transcriptional program that promotes tumor growth. At the molecular level, the binding of androgens to the AR triggers a conformational change, which promotes retention of the receptor in the nucleus and binding to specific sites in the genome. There, AR triggers the transcriptional activation of downstream target genes involved in cellular proliferation and survival. 1

Given its pivotal role in prostate cancer growth, targeting of AR signaling has been shown to inhibit tumor growth in the initial phase of recurrent disease in most patients. Traditionally, these therapeutic approaches have focused either on reducing serum androgen levels or on inhibiting the AR itself through competitive small molecule antagonists. While these singleagent therapies prove to be effective initially, the tumors inevitably develop resistance to the treatment, and patients progress to endocrine therapy-resistant or “castration-resistant” metastatic prostate cancer, with fatal outcome. 1 Importantly, castration-resistant disease continues to rely on AR signaling in most patients even in the absence of hormone stimulation from testicular androgens. Multiple mechanisms of AR re-activation have been described, including the production of intra-tumoral androgens from adrenal precursors, and genetic modifications of AR itself, which enable transactivation of the receptor under low levels of androgens. 1