Targeting aberrant circadian regulator in advanced prostate cancer

摘要 转移性前列腺癌（PCa）仍然是癌症相关死亡的主要原因之一。 转移性去势抵抗性PCa或mCRPC患者通常对第二种药物产生耐药性 包括恩杂鲁胺在内的第二代治疗剂，疾病变得致命。像许多其他 PCa肿瘤表现出高度的细胞和表观遗传可塑性， 治疗耐药性和发展为更致命的形式，如神经内分泌PC或NEPC。 昼夜节律（CR）调节主要生物过程的每日振荡。昼夜中断 (CD)被认为是一种可能的致癌物质。我们发现PCa细胞失去了正常的CR调节， CR调节因子Rev-erb α/NR1D1是生长和存活的强有力的候选驱动因子之一， mCRPC细胞我们还发现Rev-erb α在转移性CRPC中过度表达和扩增 它的小分子拮抗剂在抑制几种肿瘤的生长方面显示出很高的功效， PCa模型。我们的初步机制研究表明，Rev-erb α与几个 表观遗传因素激活与晚期PCa相关的多个基因程序。我们假设 去调节的CR调节因子如Rev-erb α通过建立异常的 染色质结构和靶向异常Rev-erb α功能的药物对 治疗致死性前列腺癌。在目标1和目标2中，我们将确立异常行为的驱动作用， Rev-erb α在肿瘤可塑性和治疗抵抗中的作用，并确定其分子机制。在目标3中， 我们将使用多种耐药CRPC模型来检查Rev-erb α的疗效 抑制剂在敏化治疗中的作用和阻断肿瘤可塑性的作用机制。

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.