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。 患有转移性去势抵抗性 PCa 或 mCRPC 的患者通常会对第二代药物产生耐药性。 一代疗法包括恩杂鲁胺，这种疾病变得致命。像许多其他人一样 癌症类型中，前列腺癌肿瘤表现出高细胞和表观遗传可塑性，这与 治疗耐药性和进展为更致命的形式，如神经内分泌 PC 或 NEPC。 昼夜节律 (CR) 调节主要生物过程的日常波动。昼夜节律紊乱 (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-erbα/NR1D1 是生长和生存的强大候选驱动力 mCRPC 细胞。我们还发现 Rev-erbα 在转移性 CRPC 中过度表达和扩增 其小分子拮抗剂在抑制多种肿瘤生长方面表现出高效 PCa 模型。我们的初步机制研究表明 Rev-erbα 与多种 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 解除对 CR 调节因子（如 Rev-erbα）的管制，通过建立异常的 染色质结构以及针对异常 Rev-erbα 功能的治疗是有效且安全的 治疗致命形式的 PCa。在目标 1 和目标 2 中，我们将建立异常的驱动角色 Rev-erbα 在肿瘤可塑性和治疗抵抗中的作用并定义了分子机制。在目标 3 中， 我们将使用多种治疗抵抗性 CRPC 模型来检查 Rev-erbα 的功效 抑制剂使治疗增敏以及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.