Targeting the androgen receptor pathway in prostate cancer

Abstract

When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration-resistant prostate cancers (CRPCs) continue to depend on androgen receptor (AR) signaling which is reactivated despite low serum androgen levels. Currently available AR-targeted therapy, including GnRH agonists and antiandrogens, cannot completely shut down AR signaling. Several mechanisms that enhance AR signaling in an androgen-depleted environment have been elucidated. These include AR mutations that allow activation by low androgen levels or by other endogenous steroids, AR overexpression, increased local intracrine synthesis of androgens, and upregulation of tyrosine kinase pathways. This has led to the development of a number of novel agents targeting the AR signaling pathway, including more effective antiandrogens, inhibitors of CYP17, an enzyme required for androgen synthesis, inhibitors of 5alpha-reductase, inhibitors of HSP90 which protects AR from degradation, inhibitors of histone deacetylases which is required for optimal AR-mediated transcription, as well as inhibitors of tyrosine kinase inhibitors. Many of these strategies are currently being tested in clinical trials in CRPC.

Figure 1

Schematic of therapeutic targets of the AR pathway. 1) AR is bound to the molecular chaparonin HSP90 which prevents its degradation. HSP90 inhibitors, such as 17-AAG, cause AR degradation and decrease AR levels. 2) In men treated with GnRH agonists to shut down testicular androgen synthesis, residual serum androgens are synthesized by the adrenal glands. In additional, evidence suggests intratumoral androgen synthesis. Both can be inhibited by the non-specific p450 inhibitor ketoconazole and the 17-lyase inhibitor abiraterone. 3) Testosterone is converted to the more potent dihydrotestosterone (DHT) by 5α-reductase, which is inhibited by finasteride and dutasteride. 4) Ligands, such as DHT bind to AR and this is inhibited by antiandrogens such as bicalutamide and novel agents MDV-3100 and BMS641988. Mutation of AR as well as AR overexpression can convert endogenous steroids (e.g., progestins, estrogens, corticosteroids) and some antiandrogens into agonists. MDV-3100 was designed to suppress AR function even when AR is overexpressed. 5) Activation of receptor tyrosine kinases, in particular HER2, can lead to downstream AR activation. Two downstream kinases that directly phosphorylate AR on tyrosine are Ack1 and SRC. Other downstream pathways of receptor tyrosine kinases, including the AKT and MAP kinase pathways, are also implicated. Antibodies such as trastuzamab and pertuzumab and small molecular TKI inhibitors such as erlotinib and lapatinib target HER2. Dasatinib target SRC. 6) Proper transcription mediated by AR requires the proper chromatin state. HDAC inhibitors inhibit transcription of AR target genes by disruption of chromatin structure and inhibition of recruitment of coactivators and RNA polymerase II.

Figure 2

Androgen synthesis pathway and therapeutic targets. Cholesterol is synthesized from Acetyl-CoA and enzymes in this pathway were found to be upregulated by Holzbeierlein et. al. (red) [10]. Subsequently, the weak androgen androstenedione, testosterone, and the potent DHT are synthesized from cholesterol and enzymes in this pathway were found to be upregulated by Stanbrough et. al. (blue) and Montgomery et. al. (orange) [22,23]. Abiraterone blocks CYP17 which contain both 17α-hydroxylase/C17,20-lyase activities (boxed orange). Dutasteride blocks both SRD5A1 and SRD5A2 (boxed green).