Therapeutic Rationales, Progresses, Failures, and Future Directions for Advanced Prostate Cancer

Abstract

Patients with localized prostate cancer (PCa) have several therapeutic options with good prognosis. However, survival of patients with high-risk, advanced PCa is significantly less than patients with early-stage, organ-confined disease. Testosterone and other androgens have been directly linked to PCa progression since 1941. In this review, we chronicle the discoveries that led to modern therapeutic strategies for PCa. Specifically highlighted is the biology of androgen receptor (AR), the nuclear receptor transcription factor largely responsible for androgen-stimulated and castrate-recurrent (CR) PCa. Current PCa treatment paradigms can be classified into three distinct but interrelated categories: targeting AR at pre-receptor, receptor, or post-receptor signaling. The continuing challenge of disease relapse as CR and/or metastatic tumors, destined to occur within three years of the initial treatment, is also discussed. We conclude that the success of PCa therapies in the future depends on targeting molecular mechanisms underlying tumor recurrence that still may affect AR at pre-receptor, receptor, and post-receptor levels.

Keywords: AR; FDA.; Prostate cancer; androgen; castrate-recurrent; treatment.

Figure 1

Structure of androgen receptor gene, transcript, and protein. (A) Relative lengths of the AR ORF and its flanking UTRs. (B) Exon structure of the AR transcript depicting the relative sizes of each exon. (C) AR protein functional domains including the NTD, DBD, hinge, and LBD and their respective coding exons. The relative locations of the AF-1, poly-glutamine (Gln), poly-glycine (Gly), NLS, NES, and AF-2 regions are indicated. Also shown are the AR protein domains to which post-translational modifications are known to occur. (D) Schematic representation of the spatial orientation of an AR homodimer complexed with a typical ARE. NTD: N-terminal domain; DBD: DNA-binding domain; LBD: Ligand-binding domain; AF-1: Activation function domain 1; NLS: Nuclear localization sequence; NES: Nuclear export signal; AF-2: Activation function domain 2; ARE: Androgen response element.

Figure 2

Activation of androgen regulated genes. Testosterone from the peripheral blood diffuses across the plasma membrane and is converted to DHT by 5α-reductase. DHT binding to AR induces HSP70 and 90 to dissociate from AR and phosphorylation of AR then promotes AR nuclear localization. In the nucleus, AR interacts with transcriptional co-regulators forming the transcriptional machinery complex that engages with AREs in the promoter regions of ARGs and triggers transcription. AR: androgen receptor; T: Testosterone; DHT: Dihydrotestosterone; HSP: Heat shock protein; ARE: Androgen response element.

Figure 3

Physiological and anatomical targets of FDA-approved drugs for prostate cancer. LHRH produced by the hypothalamus stimulates production of LH by the anterior pituitary. LH then activates the production of testosterone by the testes. Gonadal testosterone, along with testosterone produced by the adrenal glands and the prostate itself, activates transcription of ARGs. Currently approved therapies for advanced PCa target multiple nodes along this physiological pathway. LHRH: Luteinizing hormone releasing hormone; LH: Luteinizing hormone; CYP17: Cytochrome P450-C17; T: Testosterone; DHT: Dihydrotestosterone; DHEA: Dehydroepiandrosterone; AR: androgen receptor; ARE: Androgen response element.

Figure 4

Timeline representing development of therapeutic strategies for prostate cancer. Years when key discoveries were made (black) and indicated drugs (red) were FDA-approved are shown. Based on major publications and clinical advances, the chronology is broken up into three eras: pre-AR, AR, and post-AR.