Targeting aberrant circadian regulator in advanced prostate cancer

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ABSTRACT Metastatic prostate cancer (PCa) remains to be one of the leading causes of cancer-related death. Patients with metastatic castration-resistant PCa or mCRPC often develop resistance to the 2nd generation therapeutics including enzalutamide and the disease becomes deadly. Like many other cancer types, PCa tumors display high cellular and epigenetic plasticity that are associated with therapy resistance and progression to more lethal forms such as neuroendocrine PCs or NEPC. Circadian rhythm (CR) regulates daily oscillations of major biological processes. Circadian disruption (CD) is considered as a likely carcinogen. We found that PCa cells lost the normal CR regulation and that one the CR regulators Rev-erbα/NR1D1 acts as a strong candidate driver of growth and survival of mCRPC cells. We also found that Rev-erbα is overexpressed and amplified in metastatic CRPC tumors and that its small molecule antagonists displayed high efficacy in inhibition of growth of several PCa models. Our preliminary mechanistic studies suggest that Rev-erbα associates with several epigenetic factors to activate multiple gene programs associated with advanced PCa. We hypothesize that deregulated CR regulators such as Rev-erbα drives tumor plasticity by establishing aberrant chromatin structures and that targeting the aberrant Rev-erbα function is efficacious and safe for treatment of the lethal forms of PCa. In Aim 1 and Aim 2, we will establish the driver role of aberrant Rev-erbα in tumor plasticity and therapy resistance and define the molecular mechanisms. In Aim 3, we will use multiple models of therapy resistant CRPC to examine the efficacy of the Rev-erbα inhibitors in sensitizing the treatment and the mechanism of action in blocking tumor plasticity.