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。 转移性抗去势PCa或mCRPC患者通常对第二种受体产生耐药性 包括苯扎鲁胺在内的世代疗法和这种疾病变得致命。像许多其他人一样 癌症类型，PCa肿瘤表现出高度的细胞和表观遗传可塑性，与 治疗抵抗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振荡。昼夜节律紊乱 (Cd)被认为是可能的致癌物质。我们发现，前列腺癌细胞失去了正常的CR调节， 其中一个CR调节剂REV-ERBα/NR1D1是生长和生存的强有力的候选驱动因素 MCRPC细胞。我们还发现REV-ERBα在转移性癌中过表达和扩增。 肿瘤及其小分子拮抗剂对几种肿瘤的生长显示出高效的抑制作用 主成分分析模型。我们的初步机制研究表明，REV-ERBα与几个 表观遗传因子激活与晚期前列腺癌相关的多个基因程序。我们假设 去调控的CR调节器，如REV-ERBα通过建立异常来驱动肿瘤的可塑性 染色质结构和靶向异常的REV-ERBα功能是有效和安全的 致命形式的前列腺癌的治疗。在目标1和目标2中，我们将建立异常的驱动程序角色 REV-ERBα在肿瘤可塑性和治疗耐药中的作用，并明确其分子机制。在《目标3》中， 我们将使用多种耐药CRPC模型来检验REV-ERBα的疗效 抑制物在增敏治疗中的作用及其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.