AR modulators(Pfizer)

The androgen receptor (AR) plays a key regulatory role in hormone-naive, as well as in advanced, therapy-resistant prostate cancer. Therefore, the development of novel treatment strategies using new means for targeting AR function in prostate tumors aims at providing better options for control of progression and progressive disease. This review summarizes recent attempts in this field with a critical view on their clinical usefulness. In addition to classic endocrine therapy by surgical and/or chemical castration, there are concepts to inhibit the AR directly through anti-androgens, selective AR modulators, naturally occurring AR inhibitors, neutralizing antibodies and dominant-negative peptides. A unique possibility to prevent AR expression at the transcriptional level represents the use of antisense technology. The advantage of this method is that AR expression, and thus any aberrant route of its activation is prevented. Furthermore, there are several approaches by which AR signaling is inactivated indirectly. Degradation of heat-shock proteins, which direct appropriate AR protein folding, or modulation of various growth factor signaling cascades, which are thought to contribute to AR activation in the androgen-deprived patient, have been investigated.

Androgens may regulate the male skeleton either directly by stimulation of the androgen receptor (AR) or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors (ERs). To directly compare the effect of ER activation on bone in vivo with the effect of AR activation, 9-month-old orchidectomized wild-type and ER-inactivated mice were treated with the nonaromatizable androgen 5α-dihydrotestosterone, 17β-estradiol, or vehicle. Both ERα and AR but not ERβ activation preserved the amount of trabecular bone. ERα activation resulted both in a preserved thickness and number of trabeculae. In contrast, AR activation exclusively preserved the number of trabeculae, whereas the thickness of the trabeculae was unaffected. Furthermore, the effects of 17β-estradiol could not be mediated by the AR, and the effects of 5α-dihydrotestosterone were increased rather than decreased in ER-inactivated mice. ERα, but not AR or ERβ, activation resulted in preserved thickness, volumetric density, and mechanical strength of the cortical bone. ERα activation increased serum levels of insulin-like growth factor I, which were positively correlated with all the cortical and trabecular bone parameters that were specifically preserved by ERα activation but not by AR activation, suggesting that insulin-like growth factor I might mediate these effects of ERα activation. Thus, the in vivo bone-sparing effect of ERα activation is distinct from the bone-sparing effect of AR activation in adult male mice. Because these two pathways are clearly distinct from each other, one may speculate that a combined treatment of selective ER modulators and selective AR modulators might be beneficial in the treatment of osteoporosis.