Drugs targeting the arginine vasopressin receptor 1A (AVPR1A) could be repurposed for use in patients with castration-resistant prostate cancer (CRPC), according to a study in Science Translational Medicine.
Gene expression profiling of CRPC cells has identified AVPR1A as a dual target gene of androgen receptor variant 7 (AR-V7), which is constitutively active and acts as a potential driver of resistance, and its coactivator VAV3. AVPR1A copy number amplification is often observed in CRPC, and AVPR1A mRNA is increased in advanced prostate cancer compared with primary disease. AVPR1A targeting could, therefore, be a therapeutic option; an AVPR1A antagonist, relcovaptan, has been shown to be safe and efficacious in clinical trials for various disorders.
Based on these data, a team from Florida investigated the role and targeting of AVPR1A in CRPC. First, they used gene expression profiling in the CRPC cell line 22Rv1 to show that AVPR1A was the most downregulated gene after either VAV3 or AR-V7 depletion; a finding validated using VCaP xenografts in castrated severe combined immunodeficiency (SCID) mice. These data were in accordance with examination of publicly available data sets, which showed that AVPR1A mRNA is increased in advanced tumours and CRPC compared with primary tumours. Furthermore, AR+ CRPC cell lines expressed detectable AVPR1A mRNA, which was not detected in AR– cell lines or nonmaligant prostate epithelial cells.
“AVPR1A mRNA is increased in advanced tumours and CRPC compared with primary tumours”
Depletion of AVPR1A mRNA in AVPR1A-expressing CRPC cells decreased cellular proliferation; investigation of cyclin A and cleaved poly(ADP-ribose) polymerase (PARP) expression suggested that both apoptosis and cell cycle regulation might be implicated in this effect.
Stable expression of AVPR1A in androgen-dependent LNCaP cells caused them to grow rapidly in castration conditions. To demonstrate this effect in vivo, the team injected these cells into castrated nude mice and observed that AVPR1A+ tumours grew faster than controls.
They then used a preclinical xenograft model that recapitulates prostate cancer progression to study AVPR1A antagonism as a therapeutic approach. Relcovaptan administered to xenografted mice whose tumours had acquired castration resistance halted tumour growth and stabilized circulating PSA, as well as reducing Ki67 and downregulating cyclin A. Relcovaptan also reduced growth of established CRPC xenograft tumours in mouse prostates. Finally, a model of bone metastasis showed that relcovaptan decreased CRPC growth in bone and improved the bone-to-total volume ratio of tumour-bearing mouse tibias to be comparable to tumour-naive tibias.
“The impressive effects we observed using an AVPR1A antagonist in the intratibial prostate cancer xenograft model support future analysis combining taxane-based chemotherapeutics with AVPR1A antagonists,” comments corresponding author Kerry Burnstein.
The authors conclude: “Our preclinical data indicate that pharmacological targeting of AVPR1A is efficient and effective … AVPR1A inhibition had benefit for end-stage bone-metastatic CRPC, for which therapeutic options are limited.” Recent reports have described efficacy and tolerability of AVPR1A antagonism in autism spectrum disorder and support the repurposing of AVPR1A antagonists for advanced prostate cancer. Burnstein’s team also plans to evaluate effectiveness of AVPR1A antagonists in inhibiting metastatic prostate cancer growth at distal sites other than bone.
Zhao, N. et al. Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer. Sci. Transl Med. 11, eaaw4636 (2019)