Prostate cancer represents a substantial burden for American men. Androgen receptor-targeted therapy (ATT), the mainstay of treatment, is initially effective. However, prolonged ATT can induce the emergence of treatment-related neuroendocrine prostate cancer (t-NEPC), an aggressive variant prevalent in approximately 20% of lethal prostate cancer cases. Despite its increasing incidence, t-NEPC (referred to as NEPC hereafter) remains poorly understood, lethal, and lacks effective treatment options. One prominent molecular feature of NEPC cells is the constitutive activation of CREB1 signaling, the mechanism of which remains unclear. We have identified G protein-coupled receptor 6 (GPR6) as a ...

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Prostate cancer represents a substantial burden for American men. Androgen receptor-targeted therapy (ATT), the mainstay of treatment, is initially effective. However, prolonged ATT can induce the emergence of treatment-related neuroendocrine prostate cancer (t-NEPC), an aggressive variant prevalent in approximately 20% of lethal prostate cancer cases. Despite its increasing incidence, t-NEPC (referred to as NEPC hereafter) remains poorly understood, lethal, and lacks effective treatment options. One prominent molecular feature of NEPC cells is the constitutive activation of CREB1 signaling, the mechanism of which remains unclear. We have identified G protein-coupled receptor 6 (GPR6) as a promising and novel drug target, based on its substantial upregulation in NEPC patient samples, its constitutive activation, and the preliminary functional data we have obtained. GPR6 is primarily expressed in normal brain tissues at a low level, where it is known to activate CREB1 signaling. We found that GPR6 overexpression promotes aggressive phenotypes of prostate cancer cells in culture and in mouse xenografts, effects that were reversed by its silencing or inhibition. CVN424, a GPR6-specific inverse agonist (inhibitor), is deemed safe in human volunteers and is now in a Phase 2 clinical trial for Parkinson's Disease. We hypothesize that GPR6 critically contributes to aggressive phenotypes in prostate cancer progression to NEPC, which can be reversed by CVN424. We will define GPR6's role and mechanisms in NEPC cell, xenograft, and genetic mouse models, and determine the efficacy of CVN424 in various NEPC models. Our study is expected to unveil the critical role and mechanisms of GPR6 in NEPC and provide proof-of-principle for CVN424 as a potential therapeutic agent for NEPC. It holds significant promise in advancing our understanding of lethal prostate cancer and paving the way for immediate clinical trials by repurposing CVN424 for treating NEPC.

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