Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Abstract

Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.

Keywords: PARP inhibitors; Therapy; anti-androgen; castration resistant prostate cancer; epigenetic targeted treatment.

Figure 1

Schematic of the prostate epithelium and stroma. The prostate glandular structure is made up of ducts and acini. The epithelium that surrounds the lumen contains luminal, intermediate, basal, neuroendocrine and stem cells. The stroma contains extracellular matrix, immune cells, fibroblasts, neurons and smooth muscle cells.

Figure 2

The structure of the androgen receptor gene and protein. The AR gene is situated on position q11-12 of chromosome X and contains 8 exons. The protein reference sequence NM_000044.3 is comprised of 920 amino acids and is composed of different domains which are depicted. In addition, posttranslational modifications known to influence AR function are shown. AR, androgen receptor; bp, base pair; NTD, N-terminal domain; DBD, DNA binding domain; LBD, ligand binding domain; AF, activation function; TAU, transcription activation unit; NLS, nuclear localisation signal; NES, nuclear export signal.

Figure 3

Genomic androgen receptor signaling pathway. Androgens, such as testosterone and dihydrotestosterone, enter the cell and are converted in the more active metabolite (5α-DHT) by the steroid-5α-reductase. Upon ligand binding heat stress protein (HSP) chaperones are released and AR undergoes conformational change and dimerization. In the nucleus the AR together with co-regulators activates the transcription of androgen regulated genes. T, testosterone; AR, androgen receptor; DHT, 5α-dihydrotestosterone; HSP, heat shock; TF, transcription factor; ARE, Androgen Response Element.

Figure 4

Chemical structures of the endogenous androgen receptor (AR) agonists testosterone and dihydrotestosterone for comparison to AR-antagonists bicalutamide, enzalutamide, apalutamide and darolutamide.

Figure 5

Chemical structure of the KDM1A inhibitors.