Revisiting the role of antiandrogen strategies in ovarian cancer

Abstract

Androgen receptors are frequently expressed in epithelial ovarian cancer (EOC). Their role in the development of EOC is not fully understood. In the present review we first discuss the epidemiological data linking a hyperandrogen state to a higher risk for ovarian cancer, second describe in vitro studies of the role of androgens in influencing the growth of EOC, and finally review the completed clinical trials with compounds that exploit the androgen axis in patients with ovarian cancer. The therapeutic approaches that inhibit androgen signaling have so far produced only modest response rates. In the light of new data regarding the role of androgen stimulation in the evolution of EOC and the emergence of new compounds used for the treatment of other hormone-driven malignancies, such as prostate and breast cancer, we provide suggestions for new studies of antiandrogen therapeutics in the treatment of EOC. A specific example is the new agent abiraterone. In addition, we propose a panel of molecules that could be assessed as potential biomarkers that may aid patient selection for this approach in the future.

Figure 1.

Gonadotropin-releasing hormone (GnRH)–gonadotropin axis. The proposed mechanism of GnRH analogs (goserelin, triptorelin) in epithelial ovarian cancer is thought to be desensitization or downregulation of GnRH receptors in the pituitary, resulting in a decline in gonadotropin secretion and subsequent reduction in gonadal steroids including androgens.

Figure 2.

Steroid synthesis pathway and aromatization. Abiraterone is a novel cytochrome P450 (CYP)17 inhibitor that irreversibly inhibits the generation of adrenal steroids downstream of CYP17. It suppresses the generation of both androgens and estrogens. Flutamide competes with testosterone for androgen receptors (ARs), preventing their activation. Tamoxifen is an antagonist of the estrogen receptor (ER), blocking its downstream signaling. Anastrozole and letrozole block the production of estrogens by inhibiting the enzyme aromatase.