Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target

Abstract

Activation of the androgen receptor is crucial for prostate cancer growth at all points of the illness. Current therapies targeting the androgen receptor, including androgen-depletion approaches and anti-androgens, do not completely inhibit the receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes that include androgen-receptor overexpression and overexpression of enzymes involved in androgen biosynthesis, which result in reactivation of the receptor. Based on an understanding of these resistance mechanisms and androgen biosynthesis pathways, new anti-androgens and androgen-depleting agents have been developed. Notably, promising activity has been shown in early phase trials by MDV3100, a new anti-androgen designed for activity in prostate cancer model systems with overexpressed androgen receptor, and by abiraterone acetate, a CYP17A inhibitor that blocks steroid biosynthesis in the adrenal gland and possibly within the tumour. Both agents are undergoing phase 3 testing. Here, we review the basic science and clinical development of these and other agents.

Figure 1. Schematic of androgens axis and inhibitors

(Top) In men, androgens are mainly synthesized mainly by the testes as testosterone, but also in the adrenal glands as androsteinedione and dehydroepiandrosterone (DHEA). These two endocrine organs are stimulated by anterior pituitary secretion of luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH) respectively. The anterior pituitary secretion of these two hormones is themselves regulated by hypothalamic secretion of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH) respectively. Surgical castration, adrenectomy, and hypophysectomy have been performed to inhibit androgen production. Treatment with GnRH agonists and estrogens inhibits pituitary stimulation of the testes while treatment with corticosteroids inhibits pituitary stimulation of the adrenals. Abiraterone and other CYP17 inhibitors inhibit a key step in androgen synthesis, decreasing both testicular and adrenal androgen production. Circulating testosterone can be converted to the more potent dihydrotestosterone (DHT) in prostate cancer by 5α-reductase, a process that is inhibited by dutasteride. (Bottom) Androgens exert their effects on prostate cancer cells by binding and activating the androgen receptor (AR). MDV3100 and other antiandrogens competitively inhibit the binding of the AR by agonists. When bound to MDV3100, AR does not bind DNA required to activate transcription.

Figure 2. Clinical states where AR directed therapies are used

In patients with rising PSA or metastatic disease, initial treatment usually consists of ADT, usually by GnRH agonists. Antiandrogens can be added to ADT during initial treatment, often termed “Combined Androgen Blockade” or “Maximum Androgen Blockade”. More commonly antiandrogens or ketoconazole is added when patients progress on ADT into CRPC (“TYPICAL”). Docetaxel is the only treatment shown to prolong survival in CRPC. After progression on doctaxel, there is no effective treatement. MDV3100 and abiraterone have shown promising activity in both chemotherapy-naïve “TYPICAL” and post-docetaxel “ATYPICAL” CRPC patients. Currently, both agents are in phase III trials of post-docetaxel patients randomized to placebo with overall survival as the primary endpoint.

Figure 3. Chemical Structures of antiandrogens and CYP17 inhibitors

A) First and second generation non-steroidal antiandrogens as well as the novel compound BMS 641988 share a toliudide backbone with increasing bulk. MDV3100 is a non-steroidal antiandrogen with a thiohydantoin backbone. Cyproterone actetate (CPA), abiraterone, and VN/124-1 are all steroidal compounds similar to progesterone. CPA is an antiandrogen with partial agonist properties; abiraterone is an irreversible inhibitor of CYP17, and VN/124-1 both inhibits both CYP17 and binds AR and causes its degradation. B) The steroid synthesis pathway starts with the generation of pregnenolone from cholesterol. CYP17 and 3β-HSD are present in both adrenal glands and testes and generates weak androgens androsteinedione and DEAS. 17-ketoreductase in the testes further generates testosterone. In peripheral tissues, testosterone is converted to the more potent DHT by 5α-reductase. In CRPC, the enzymes involved in androgen synthesis (CYP17, 3β-HSD, 17-ketoreductase, 5α-reductase) have been found to be cancer cells (4, 7, 40).

Figure 4. Schematic of AR activation and antiandrogen mechanism

AR consists of N-terminal domain with ligand-independent activation functions (NTD), a DNA binding domain (DBD), followed by ligand binding domain (LBD). HSP90 binds to LBD of Apo-AR and stabilizes the protein. Androgen binding causes dissociation from HSP90, conformation change in the LBD that allows intramolecular binding to the NTD and intermolecular binding to coactivators, nuclear translocation, and DNA binding. When bicalutamide and other available antiandrogens bind AR, nuclear translocation is preserved and DNA binding and coactivators recruitment occurs when AR is overexpressed. When MDV3100 binds AR, nuclear translocation is inefficient and DNA binding and coactivators recruitment is completely inhibited.

Figure 5. Activity of MDV3100

A) AR localizes in the cytoplasm in the absence of ligand and almost completely translocates to the nucleus when bound to the synthetic androgen R1881 or bicalutamide. When bound to MDV3100, nuclear translocation is incomplete (adopted from Tran et al, permission from Science). B) In prostate cancer cells that overexpress AR, R1881 and bicalutamide stimulates AR binding to the PSA enhancer region PSA production whereas MDV3100 does not (adopted from Tran et al, permission from Science).