Therapeutic Approaches to Targeting Androgen Receptor Splice Variants

Abstract

Therapeutic options for advanced prostate cancer have vastly expanded over the last decade and will continue to expand in the future. Drugs targeting the androgen receptor (AR) signaling pathway, i.e., androgen receptor targeting agents (ARTAs), remain the mainstream treatments that are increasingly transforming the disease into one that can be controlled for an extended period of time. Prostate cancer is inherently addicted to AR. Under the treatment pressure of ARTA, molecular alterations occur, leading to the clonal expansion of resistant cells in a disease state broadly categorized as castration-resistant prostate cancer (CRPC). One castration resistance mechanism involves AR splice variants (AR-Vs) lacking the ligand-binding domain. Some AR-Vs have been identified as constitutively active, capable of activating AR signaling pathways without androgenic ligands. Among these variants, AR-V7 is the most extensively studied and may be measured non-invasively using validated circulating tumor cell (CTC) tests. In the context of the evolving prostate cancer treatment landscape, novel agents are developed and evaluated for their efficacy in targeting AR-V7. In patients with metastatic CRPC (mCRPC), the availability of the AR-V7 tests will make it possible to determine whether the treatments are effective for CTC AR-V7-positive disease, even though the treatments may not be specifically designed to target AR-V7. In this review, we will first outline the current prostate cancer treatment landscape, followed by an in-depth review of relatively newer prostate cancer therapeutics, focusing on AR-targeting agents under clinical development. These drugs are categorized from the standpoint of their activities against AR-V7 through direct or indirect mechanisms.

Keywords: AR-V7; androgen receptor splice variants; castration-resistant prostate cancer.

Figure 1

AR-FL vs. AR-V7 Protein Functional Domains. AR-V7 lacks most of the hinge region and the entire ligand binding domain present in AR-FL. The figure is not drawn to scale. Source: Adapted from Figure 1 of the Luo 2016 review [10]. Numbers indicate amino acid (AA) numbers. Protein length slightly varies among literatures due to the variation in CAG repeat numbers in NTD. The amino acid position annotations in this figure are based on NP_000035.2 for AR-FL and NP_001334990.1 for AR-V7. AR-V7 protein possesses a 16-AA AR-V7-specific peptide at its C-terminal end.

Figure 2

Prostate Cancer Systemic Treatment Landscape. This flow chart shows the standard progression through available treatment options for varying disease statuses as of 2023. Clinical trial options are not included. The information presented is subject to change pending future drug approvals. ADT: androgen-deprivation therapy; BCR: biochemical recurrence; local Tx: local treatment such as radiation or surgery; mCRPC: metastatic castration-resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; nmCRPC: non-metastatic castration-resistant prostate cancer; PC: prostate cancer.

Figure 3

Direct Targeting of AR-V7. This figure provides a brief overview of the mechanisms of action of the compounds that directly target AR-V7, as shown in Table 1. ?: The mechanism of action of TAS3681 is yet to be published.

Figure 4

Mechanisms of Indirectly Targeting AR-V7. This figure provides an abbreviated overview of the mechanisms of action of the therapies that indirectly target AR-Vs, as shown in Table 2.