Rationale for the development of alternative forms of androgen deprivation therapy

Abstract

With few exceptions, the almost 30,000 prostate cancer deaths annually in the United States are due to failure of androgen deprivation therapy. Androgen deprivation therapy prevents ligand-activation of the androgen receptor. Despite initial remission after androgen deprivation therapy, prostate cancer almost invariably progresses while continuing to rely on androgen receptor action. Androgen receptor's transcriptional output, which ultimately controls prostate cancer behavior, is an alternative therapeutic target, but its molecular regulation is poorly understood. Recent insights in the molecular mechanisms by which the androgen receptor controls transcription of its target genes are uncovering gene specificity as well as context-dependency. Heterogeneity in the androgen receptor's transcriptional output is reflected both in its recruitment to diverse cognate DNA binding motifs and in its preferential interaction with associated pioneering factors, other secondary transcription factors and coregulators at those sites. This variability suggests that multiple, distinct modes of androgen receptor action that regulate diverse aspects of prostate cancer biology and contribute differentially to prostate cancer's clinical progression are active simultaneously in prostate cancer cells. Recent progress in the development of peptidomimetics and small molecules, and application of Chem-Seq approaches indicate the feasibility for selective disruption of critical protein-protein and protein-DNA interactions in transcriptional complexes. Here, we review the recent literature on the different molecular mechanisms by which the androgen receptor transcriptionally controls prostate cancer progression, and we explore the potential to translate these insights into novel, more selective forms of therapies that may bypass prostate cancer's resistance to conventional androgen deprivation therapy.

Androgen receptor co-regulation in prostate cancer

“…Nonetheless, the presence of canonical AREs, usually defined as 15 bp full-length sequence, ranged from about 2.5% to 54% among studies [ [34] , [35] , [36] , [37] , [38] , [39] ]. These studies suggested also that AR binding to AREs allows for one to three bases degeneration in the consensus ARE motif, differences in orientation of the hexamer half sites, more variable spacing between these half sites, or in some cases just one ARE half site/hexamer, the latter possibly in combination with recognition motifs for other transcription factors such as FoxA1 [ 12 ]. In addition to liberty in the specific sequence of DNA motif to which AR binds, it is now clear that the scope and composition of the AR cistrome, i.e.…”

“…Like many transcription factors, AR relies on functional and structural interactions with other transcriptional regulators to ensure proper transcription of its target genes [ 12 , 15 ]. Some of these AR-associated proteins clearly display the characteristics of a coregulator, i.e.…”

“…Similarly, considerable functional variability has been noted also for the transcription factors that help regulate AR's transcriptional output. Some bind their own recognition motifs in close proximity (range: 0–1000 bp) of AR binding peaks, while others are recruited to AR as cofactor, or both [ 12 , 15 ]. In addition to transcription factors that are more broadly involved in regulation of gene expression such as AP1 or Sp1 [ 15 ], AR interacts also with other more specialized factors such as the stem cell transcription factor Nanog [ 53 ].…”

“…Although Nanog is not typically thought of as having major roles in the endocrine response of adenocarcinoma cells, the enrichment for Nanog binding sites close to some AREs has been independently confirmed [ 52 ]. Analyses of protein-protein and protein-DNA interactions and DNA sequences nearby AREs, support involvement of dozens of functionally diverse transcription factors in regulating the AR transcriptional complex [ 12 , 15 ]. In clinical PCa, it has long been recognized that multiple AR-associated coregulators are differentially expressed, and mostly overexpressed, compared to benign prostate tissue.…”

“…Other approaches have been designed to disrupt the interaction between AR and AR-associated coregulators or secondary transcription factors, or to directly target the activity of such AR-collaborators that are essential to achieve its full transcriptional output. The latter efforts have yielded a multitude of peptides, peptidomimetics, small molecule inhibitors [ 12 ]. Most of these showed promise as PCa therapeutics when tested preclinically, and several are currently in or have completed clinical trials.…”