Targeting aberrant circadian regulator in advanced prostate cancer

针对晚期前列腺癌的异常昼夜节律调节剂

• 批准号: 10541250
• 负责人: Hongwu Chen
• 金额: $ 35.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541250
• 关键词: ASCL1 gene; Acetylation; Automobile Driving; Biological Assay; Biological Process; Cancer Etiology; Carcinogens; Cell Lineage; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Structure; Circadian Dysregulation; Circadian Rhythms; Complex; DNA Binding; Data; Disease; Drug resistance; Epigenetic Process; Gene Activation; Generations; Genes; Genetic Transcription; Genomic approach; Growth; In Vitro; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolism; Metastatic Prostate Cancer; Modeling; Molecular; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Patients; Pharmaceutical Preparations; Proteins; Regulation; Regulator Genes; Resistance; Resistance development; Risk; Role; Safety; Series; Site; Squamous Cell Lung Carcinoma; Testing; Therapeutic; Time; advanced prostate cancer; antagonist; cancer stem cell; cancer subtypes; cancer type; castration resistant prostate cancer; chromatin modification; circadian; circadian pacemaker; effective therapy; efficacy evaluation; enzalutamide; in vivo; inhibitor; innovation; insight; knock-down; men; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; pancreatic cancer cells; patient derived xenograft model; programs; prostate cancer cell; prostate cancer model; recruit; small molecule; small molecule inhibitor; stem-like cell; success; therapeutic development; therapeutic target; therapeutically effective; therapy resistant; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumorigenic

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.

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-erbα/NR 1D 1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-erbα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-erbα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-erbα通过建立异常的 染色质结构和靶向异常Rev-erbα功能的药物对 治疗致死性前列腺癌。在目标1和目标2中，我们将确立异常者的驱动者角色 Rev-erbα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-erbα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。