Abstract
In prostate cancer (PC), androgen deprivation therapy remains the gold standard for treatment of high risk or advanced disease, but unfortunately PC typically recurs as castration-resistant prostate cancer (CRPC). CRPC is incurable and thus new therapies that exploit actionable targets are needed. Our lab identified the Arginine Vasopressin Receptor Type 1A (AVPR1A) as a therapeutic target in CRPC. AVPR1A is part of a G protein-coupled receptor (GPCR) family which includes Arginine Vasopressin Receptor Type 2 (AVPR2), with arginine vasopressin (AVP) as their endogenous ligand. AVPR1A stimulates intracellular calcium release through the Gα subunit Gq/11, while AVPR2 increases intracellular cAMP through the Gα subunit Gαs and canonically activates phosphokinase A (PKA).
Interrogation of patient sample data sets revealed that AVP expression is upregulated in advanced metastatic forms of prostate cancer compared to less aggressive, localized disease. Additionally, CRPC cells were found to produce AVP and require AVP production for optimal proliferation. AVPR1A and AVPR2 co-expression correlating in advanced prostate cancer and CRPC production of AVP indicate a potential mechanism for CRPC growth driven by AVPR1A/AVPR2 mediated autocrine/paracrine signaling.
Combined suboptimal doses of AVPR1A and AVPR2 antagonists were evaluated in vitro and synergistically inhibited CRPC cell growth as well as increased cell death with no effect on non-tumorigenic prostate epithelial cells. Additionally, inhibition of AVPR1A and AVPR2, individually or together, with selective antagonists reduced tumor size in vivo while having no obvious effect on mouse health. These findings implicate a novel mechanism for CRPC-tumor microenvironment crosstalk through cancer-produced AVP acting both on the tumor itself in an autocrine fashion and potentially in a paracrine fashion on the surrounding tumor microenvironment. This novel mechanism, the AVP/AVPR1A/AVPR2 signaling axis, is an exploitable target for repurposing clinically safe and effective compounds to treat CRPC.