Research ArticleCancer

Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer

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Science Translational Medicine  26 Jun 2019:
Vol. 11, Issue 498, eaaw4636
DOI: 10.1126/scitranslmed.aaw4636

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Solving cancer’s (vaso)pressing problem

Castration-resistant prostate cancer is a lethal late-stage form of prostate cancer, where the tumor can grow independently and no longer requires external stimulation of the androgen receptor. Zhao et al. found that the arginine vasopressin receptor 1a, which is normally associated with maintenance of blood pressure and fluid balance, can help activate signaling pathways involved in the development of castration resistance in prostate cancer. An antagonist of this receptor, relcovaptan, which can be safely used in humans, showed promising activity in mice modeling different stages of prostate cancer, suggesting this drug’s potential for repurposing if its effects are confirmed in clinical studies.

Abstract

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein–coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

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