Jay Hofweber

Introduction. Prostate cancer (PC) is the second-leading cause of cancer-related death among males in the United States.¹ 10-20% of prostate cancer patients develop castration-resistant prostate cancer (CRPC) within approximately 5 years with a median survival from 9 to 30 months.² Progression to CRPC results from failure of androgen deprivation therapy (ADT), which targets the androgen receptor (AR) signaling axis. AR-targeting therapies, such as abiraterone and enzalutamide, dampen AR signaling in CRPC.³ Constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in CRPC.⁴ AR-V7 lacks the AR ligand–binding domain (LBD), but continues to signal through its transcriptionally active N-terminal domain facilitating ligand independent AR signaling in CRPC and treatment resistance.⁵ Methods. Utilizing a novel AR-V7 antibody for IHC, AR-V7 protein expression was evaluated for 358 primary prostate samples and 293 metastatic biopsies to determine associations with disease progression. AR-V7 cistromes were identified in human CRPC patient tissues by using a ChIP exonuclease sequencing approach with a specific antibody targeting endogenous AR-V7. IHC for BRD4, AR-V7, and full-length AR (AR-FL) was performed on patient samples and the mechanism by which chemical BETi regulates AR-V7 expression was studied in prostate cancer models. LNCaP and 22Rv1 cells were transfected with plasmid encoding AR-FL or AR-V7 to investigate if melatonin could inhibit the AR-V7-induced IL-6 gene expression in LNCaP and 22RV1 cells. Results. AR-V7 protein is expressed <1% in primary PC but is detected in 75% of cases following ADT, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy.⁴ AR-V7 expression correlates with HoxB13, a critical coregulator of AR-V7 function which collaborates with AR-V7 to up-regulate target oncogenes.^4,6 HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function.⁶ BRD4 protein expression increases significantly (P <0.01) with castration resistance in same patient treatment-naïve and CRPC biopsies.⁵ Chemical BETi reduce AR-V7 expression and AR signaling.⁵ In LNCaP and 22Rv1 prostate cancer cells overexpressing AR-V7, nuclear factor-kappa B (NF-kB) was activated and could result in up-regulated IL-6 gene expression. Both AR-V7-induced NF-kB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin.⁷ Conclusion. HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.⁶ BETi merit clinical evaluation as inhibitors of AR splicing and function in pharmacological studies.⁵ Melatonin therapy in CRPC management is worth translation in the clinic combined with androgen depletion.⁷

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3. Liu VWS, Yau WL, Tam CW, Yao KM, Shiu SYW. “Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.” Int J Mol Sci. 2017 May 31;18(6). pii: E1130. doi: 10.3390/ijms18061130.
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5. Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, et. al. “Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)” Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571.
6. Chen Z, Wu D, Thomas-Ahner JM, Lu C, Zhao P, et. al. “Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13” Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6810-6815. doi: 10.1073/pnas.1718811115.
7. Liu VWS, Yau WL, Tam CW, Yao KM, Shiu SYW. “Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.” Int J Mol Sci. 2017 May 31;18(6). pii: E1130. doi: 10.3390/ijms18061130.