Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors

Abstract

Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1 dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men

“…The Physicians' Health Study confirmed the starting hypothesis, namely that testosterone and dihydrotestosterone (DHT) were positively associated with estradiol, and that sex hormone binding globulin was inversely associated with prostate cancer (Gann PH et al 1996). In recent years, several clinical studies of hormone treatment for prostate cancer have been done (Cai C et al 2011;Chang KH et al 2011;Mostaghel EA et al 2011;Richards J et al 2012;Mostaghel EA 2013). Prostate-specific antigen (PSA) is a glycoprotein produced almost exclusively by the epithelial cells of the prostate gland, and is used as a marker for the diagnosis and monitoring of prostate cancer (Hudson MA et al 1989;Oesterling JE 1991;Armbruster DA 1993).…”

“…Furthermore, DHEA (which is synthesized by the adrenal glands through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1) makes CYP17A1 inhibitors such as abiraterone effective therapy for castration-resistant prostate cancer (Cai C et al 2011). A recent study found an inverse correlation between serum levels of TCDD and testosterone in US veterans of the Vietnam War (Gupta A et al 2006).…”

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

“…Further details of instrument set up are included in Supplementary Methods for reference. Both the TSQ Vantage and 4000 QTRAP were operated in SRM mode to selectively measure the following AR peptides: GAFQNLFQSVR (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and LLDSVQPIAR (862-871). The unlabeled, "heavy" labeled ( 13 C 6 , 15 N 4 R, þ10 Da), and "medium" labeled ( 13 C 6 , þ6 Da) forms of both peptides were measured in parallel.…”

“…However, although the activity of these agents in CRPC is very encouraging, neither works in all patients and both are associated with the development of additional resistance. Although the mechanisms by which tumors become refractory to abiraterone acetate and enzalutamide treatment have not yet been clearly elucidated, current clinical (4,25) and preclinical (26)(27)(28) data suggest that re-activation of the AR will remain a primary mechanism. Thus, there is a continued need to identify alternative therapies for the treatment of CRPC, and in particular those that have a mechanistically distinct inhibitory effect on AR signaling.…”

Beyond Castration—Defining Future Directions in the Hormonal Treatment of Prostate Cancer

“…To date, despite intensive speculation, there are only limited data available to suggest pathways that mediate resistance. Cai et al characterized abiraterone resistance in a murine model and found that the emergence of resistant VCaP cell lines was associated with an upregulation of the CYP17 enzyme [23]. Overcoming CYP17 upregulation could possibly be achieved with increasing doses of abiraterone or more potent CYP17 inhibitors, however this will incur greater mineralocorticoid side effects, and is likely to be temporary.…”