Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

Abstract

Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

“…Inhibitors (e.g. abiraterone) targeting the androgen biosynthetic enzyme CYP17 have shown significant activity in patients with CRPC (8,9).…”

The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

“…There has indeed been a great deal of excitement in the oncology field over recent success in going beyond the initial use of general steroid biosynthesis inhibitors, such as ketoconazole 7 , and testing of newer CYP17A1 inhibitors, such as abiraterone 8; 9; 10 to limit DHEA biosynthesis. Recent trials have suggested that the CYP17A1 inhibition strategy is indeed successful, with ~ 5 months of additional overall survival accruing to subjects receiving abiraterone who had already developed castration resistant prostate cancer 11; 12; 13; 14; 15 . There is, nevertheless, a major problem that remains to be overcome; while tumor cells develop steroid producing ability of their own, as in the case of prostate cancer 10; 13; 14; 15 , they are not the major biosynthetic source of steroid hormones in the body.…”

“…Recent trials have suggested that the CYP17A1 inhibition strategy is indeed successful, with ~ 5 months of additional overall survival accruing to subjects receiving abiraterone who had already developed castration resistant prostate cancer 11; 12; 13; 14; 15 . There is, nevertheless, a major problem that remains to be overcome; while tumor cells develop steroid producing ability of their own, as in the case of prostate cancer 10; 13; 14; 15 , they are not the major biosynthetic source of steroid hormones in the body. That title is clearly claimed by the adrenal, which dwarfs steroidogenic output by testes, ovaries or other organs, including adipose and the brain.…”

Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review

“…For most patients, AR signaling remains the primary oncogenic driver despite castrate testosterone levels, and its activation has been observed to be mediated through a multitude of mechanisms [3,6,7]. In this article, we review the major mechanisms through which AR signaling is sustained, including AR gene amplification and overexpression, AR mutations, constitutively active AR splice variants, and intratumoral androgen synthesis.…”