Laura Schulz

Background: Castration resistant prostate cancer (CRPC) is prostate cancer that persists after androgen deprivation therapy. Traditional prostate cancer proliferates when androgens bind to the androgen receptor, so treatments include androgen deprivation therapy. This creates castration conditions, and if the cancer continues to progress it is considered CRPC. 10-20% of prostate cancers progress to CRPC, and it is more aggressive with increased mortality.^1,2 Also, CRPC is associated with a poorer prognosis and fewer effective treatments.³ Changes in androgen receptors and signaling leads to CRPC, like truncated splice variant 7 of the androgen receptor (AR-V7).¹ AR-V7 is constitutively active, meaning it does not rely on the presence of androgens to allow proliferation of CRPC.⁶ AR-V7 signaling also contributes to bone metastasis and epithelial-to-mesenchymal transition and is also associated with resistance to certain therapeutic options, like taxane chemotherapies, abiraterone and enzalutamide.^6,7,8 Knowing that AR-V7 contributes to CRPC, the next step is to determine whether it is an appropriate target for treatment.

Objective: In this narrative review, we explored properties of AR-V7 to determine if targeting AR-V7 is a viable strategy for the treatment of CRPC.

Search Methods: An online search in the PubMed database was conducted from 2018-2026 using the following key words: “castration resistant prostate cancer”, “androgen receptor splice variant 7”, “AR-V7”, “treatment”.

Results: Studies show that AR-V7 has a unique Dimerization domain (D-Box).⁷ In AR-V7, the D-box is required for nuclear localization, and without it, it is isolated to the cytoplasm and transcriptionally inactive. Studies using in-vivo mice models demonstrated that AR-V7 expression contributed to increased bone lesion area, driving bone metastasis.⁶ Using immunostaining they determined that it was via SOX9 gene expression, and using RNA-sequencing Gene Set Enrichment Analysis found that AR-V7 activates genes related to the epithelial-mesenchymal transition, which contributes to metastasis.⁶ Looking forward to future treatment options, researchers developed an autophagy targeting chimera (AUTOTAC) to target androgen receptor and variants, specifically AR-V7 and found that it did induce cell death in CRPC lines positive for androgen receptors.⁸ Another current treatment option for CRPC is Niclosamide, which was originally known as an anti-parasitic drug. Studies show that niclosamide targets AR-V7 by increasing its proteasomal degradation.¹¹ They also found that niclosamide can be used to resensitize cells to other forms of treatment to which it was previously resistant. This concept was used to develop a clinical trial where niclosamide and abiraterone/prednisone combination therapy were delivered to 9 patients.¹⁰ They found that 5 out of the 9 patients were responsive to therapy, and 2 patients had a complete response, indicated by PSA levels <0.2 ng/mL.¹⁰

Conclusions: AR-V7 is an important contributor to CRPC, and research highlighting its unique functions, like the D-box domain, and various methods of targeting it, like the AUTOTAC, could be critical for future treatments. Targeting AR-V7 in combination therapies appears useful in the clinical trial, although limited by sample size. Overall, understanding how AR-V7 contributes to CRPC will guide the future towards new and more effective treatment options for these patients.

Works Cited:

1. Jordan E. Vellky, William A. Ricke, Development and prevalence of castration-resistant prostate cancer subtypes, Neoplasia, Volume 22, Issue 11, 2020, Pages 566-575, ISSN 1476-5586, https://doi.org/10.1016/j.neo.2020.09.002. (https://www.sciencedirect.com/science/article/pii/S1476558620301482)
2. Wallace KL, Landsteiner A, Bunner SH, Engel-Nitz NM, Luckenbaugh AN. Increasing prevalence of metastatic castration-resistant prostate cancer in a managed care population in the United States. Cancer Causes Control. 2021 Dec;32(12):1365-1374. doi: 10.1007/s10552-021-01484-4. Epub 2021 Aug 12. PMID: 34386852.
3. Lin TT, Chen YH, Wu YP, Chen SZ, Li XD, Lin YZ, Chen SH, Zheng QS, Wei Y, Xu N, Xue XY. Risk factors for progression to castration-resistant prostate cancer in metastatic prostate cancer patients. J Cancer. 2019 Sep 7;10(22):5608-5613. doi: 10.7150/jca.30731. PMID: 31632505; PMCID: PMC6775699.
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8. Bae TH, Sung KW, Pham TM, Najy AJ, Zamiri A, Jang H, Mun SR, Kim S, Kwon HK, Son YS, Shi D, Kregel S, Heath EI, Cher ML, Kwon YT, Kim HC. An Autophagy-Targeting Chimera Induces Degradation of Androgen Receptor Mutants and AR-v7 in Castration-Resistant Prostate Cancer. Cancer Res. 2025 Jan 15;85(2):342-359. doi: 10.1158/0008-5472.CAN-24-0591. PMID: 39531508; PMCID: PMC11733533.
9. Kim MY, Jung AR, Shin D, Kwon H, Cho HJ, Ha US, Hong SH, Lee JY, Kim SW, Park YH. Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer. Am J Cancer Res. 2021 Jun 15;11(6):2944-2959. PMID: 34249437; PMCID: PMC8263667.
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