Medical or surgical castration serve as the backbone of systemic therapy
for advanced and metastatic prostate cancer, taking advantage of the importance
of androgen signaling in this disease. Unfortunately, resistance to castration
emerges almost universally. Despite the development and approval of new and more
potent androgen synthesis inhibitors and androgen receptor (AR) antagonists,
prostate cancers continue to develop resistance to these therapeutics, while
often maintaining their dependence on the AR signaling axis. This highlights the
need for innovative therapeutic approaches that aim to continue disrupting AR
downstream signaling, but are orthogonal to directly targeting the AR itself. In
this review, we discuss the preclinical research that has been done, as well as
clinical trials for prostate cancer, on inhibiting several important families of
AR interacting proteins, including chaperones (such as HSP90 and FKBP52),
pioneer factors (including FOXA1 and GATA-2), and AR transcriptional
coregulators such as the p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2,
SRC-3, as well as lysine deacetylases (KDACs) and lysine acetyltransferases
(KATs). Researching the effect of, and developing new therapeutic agents that
target, the AR signaling axis is critical to advancing our understanding of
prostate cancer biology, and to continuing to improve treatments for prostate
cancer and for overcoming castration-resistance.