A profile of enzalutamide for the treatment of advanced castration resistant prostate cancer

Abstract

Recent advances in understanding the mechanisms underlying the development and progression of castration resistant prostate cancer from androgen-sensitive prostate cancer have provided new avenues exploring efficacious therapies in a disease which is the second leading cause of cancer deaths among men in the western world. In the evolution of second generation anti-androgens, enzalutamide, a novel androgen-receptor signaling inhibitor, has emerged targeting multiple steps within the androgenic stimulation pathway. This review discusses what is currently known of the mechanisms surrounding castration resistant prostate cancer development and the current human clinical trials to determine whether enzalutamide presents a new hope for men with advanced prostate cancer. The issues of therapy resistance, withdrawal effects and cross-resistance are briefly touched upon.

Keywords: MDV3100; androgen receptor; anti-androgen; enzalutamide; metastatic castrate resistant prostate cancer.

Figure 1

Androgen receptor (AR) gene, protein and its constitutively active variants. Notes: (A) Full-length AR gene and protein. The AR gene consists of eight exons. Exon 1 codes for the amino-terminal domain (NTD), which contains the AF1 transactivation function. Exon 2 and 3 code for the DNA-binding domain (DBD). The hinge region (H) which contains the nuclear localization signal is encoded by the 5′ region of exon 4. The 3′ region of exon 4 alongside 5–8 encodes for the ligand-binding domain (LBD), which consists of the second transactivation function AF-2. (B) AR splice variants. The two major AR splice variants readily detectable in castration resistant prostate cancer specimens, AR-V7 and AR-V12 (also known as AR3 and AR-V^e567s, respectively) have the ability to regulate target gene expression in the absence of full-length AR signaling. Gene expression profiles revealed that these variants regulate genes responsible for cell cycle function as well as androgen-responsive genes. AR-V7 is truncated at the end of exon 3 and lacks the LBD, however contains amino acids from cryptic exon 3 (CE3). AR-V12 splice variant is missing exons 5–7, which left the protein with only a small part of the LBD region which is not located at the normal translation frame. AR-V12 is one of the most frequent AR splice variants found in 23% of human bone metastasis. It is thought to be responsible for poor disease prognosis, however its precise role remains unknown.

Figure 2

Mechanism of castrate-resistant prostate cancer. Notes: 1) Androgens bind and activate the AR despite the castration of testes-derived androgens. Androgens are secreted from other sources such as adrenal glands, adipose tissue, and intratumoral testosterone production.– 2) Prostate cancer cells become sensitized to low levels of circulating androgens post-castration by increasing the production of AR via gene amplification and by increasing the local conversion of testosterone to potent dihydrotestosterone (DHT) via 5alpha-reductase.– 3) Promiscuous pathway. Mutations (mostly missense) of the LBD of AR expand the binding specificity, allowing non-androgenic steroids, such as estrogen (E), progesterone (P), and glucocorticoid (G) to bind and activate the AR.– 4) Alternative splicing within the NTD or LBD of the AR gene allows the AR protein to translocate and bind the DNA without the need for ligand binding or dimerization., Some AR splice variants promote castration resistance and anchorage-independent growth through coupling to the full-length AR mRNA production. 5) Alteration of the levels of coactivators and co-repressors, signaling intermediates between the AR and transcriptional machinery, affect the AR activation by sensitizing to lower levels of androgen and alternative activation mechanisms.– 6) Bypass pathway. Prostate cancer cells develop the ability to evade apoptosis and survive when exposed to low levels of androgen via upregulation of the molecule Bcl-2, a regulator of programmed cell death.– 7) Stem cell regeneration may continually supply the androgen-independent population of prostate cancer cells after ADT.– Abbreviations: AR, androgen receptor; LBD, ligand binding domain; NTD, amino-terminal domain; ADT, androgen deprivation therapy; CRPC, castration resistant prostate cancer; PSA, prostate-specific antigen; mRNA, messenger RNA; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone.

Figure 3

Summary of the search strategy. Notes: *“Castrate resistant prostate cancer”, “CRPC”, “Enzalutamide”, “MDV3100”, “study”, “trial”, “safety”, “maximum tolerated dose”, and “side effect*”. Abbreviation: CRPC, castration resistant prostate cancer.