CYP17A1 inhibitors in castration-resistant prostate cancer

Abstract

The majority of prostate cancer (PCa) cases are diagnosed as a localized disease. Definitive treatment, active surveillance or watchful waiting are employed as therapeutic paradigms. The current standard of care for the treatment of metastatic PCa is either medical or surgical castration. Once PCa progresses in spite of castrate androgen levels it is termed 'castration-resistant prostate cancer' (CRPC). Patients may even exhibit rising PSA levels with possible bone, lymph node or solid organ metastases. In 2010, the only agent approved for the treatment of CRPC was docetaxel, a chemotherapeutic agent. It is now known that cells from patients with CRPC express androgen receptors (AR) and remain continuously influenced by androgens. As such, treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront. The use of cytochrome P450c17 (CYP17A1) inhibitor underlies one of the most recent advances in the treatment of CRPC. Abiraterone acetate (AA) was the first CYP17A1 inhibitor approved in the United States. This review will discuss CRPC in general with a specific focus on AA and novel CYP17A1 inhibitors. AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy. Furthermore, the most recently identified CYP17A1 inhibitors Orteronel, Galeterone, VT-464, and CFG920 will also be explored.

Keywords: Abiraterone; Castration resistance; Prostate cancer.

Figure 1. Advanced prostate cancer treatment targets

Gonadotropin releasing hormone (GnRH) agonist and antagonist inhibit the synthesis of androgens by blocking the release of gonadotropins from the pituitary. Ketoconazole (keto) and CYP17A1 Inhibitors block the synthesis of adrenal androgens to further decrease the amount of available testosterone (T) and other weak androgens that can potentially activate AR. In addition, 5α-reductase (5αR) inhibitors can be used to block the conversion of T to the more potent androgen, dihydrotestosterone (DHT), and AR inhibitors can prevent the binding of any remaining ligand. Phoshoinositide-3-Kinase (PI3K), Protein Kinase B (AKT), and Tyrosine Kinase (TK) inhibitors block alternative signaling pathways leading to activation of AR in the absence of ligand. Finally, heat shock protein (HSP) inhibitors are being studies as these can induce AR activation and nuclear localization independently of ligand (HSP90) and can protect cells against apoptosis (HSP27).

Figure 2. Steroid and Adrenal Androgen Synthesis Pathway

Key steps for the synthesis of steroids and adrenal androgens are shown along with the enzymes inhibited by drugs used for treatment of CRPC including ketoconazole (Keto) and CYP17A1 inhibitors: Abiraterone acetate (AA), Orteronel (Ort), Galetertone (Gal), VT464, and CFG920. CYP17A1 catalyzes the conversion of pregnenolone to 17α-pregnenolone and progesterone to 17α-hydroxyprogesterone through its 17α-hydroxylase activity pulling steroids down the pathway for androgen synthesis. In addition, CYP17A1 catalyzes the final steps in androgen synthesis through its C17,20-lyase activity, converting 17α-hydroxypregnenolone to dehydroepiandrosterone (DHEA) and 17α -hydroxyprogestrone to androstenedione. The enzyme 3β-Hydroxysteroid Dehydrogenase (3β-HSD) is also important in androgen production as it catalyzes the conversion of DHEA to androstenedione.