Identifying the Drivers and Targeting Chemo Resistance in Ovarian Cancer

确定卵巢癌的驱动因素并针对化疗耐药性

• 批准号: 9330488
• 负责人: Mazhar Adli
• 金额: $ 42.92万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330488
• 关键词: Automobile Driving; Biology; Cell Line; Cells; ChIP-seq; Chromatin; Cisplatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Data; Development; Disease; Distal; Enhancers; Epigenetic Process; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genome; Genomic Segment; Goals; In Vitro; Knock-out; Knowledge; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Mediating; Molecular Profiling; Outcome; Ovarian; Patients; Pharmacology; Phenotype; Platinum; Process; Recurrence; Regulation; Research; Resistance; Role; Sampling; Serous; Site; System; Testing; Therapeutic; Time; Treatment Efficacy; Work; Xenograft Model; Xenograft procedure; base; cancer cell; chemotherapy; clinically relevant; combinatorial; epigenome; epigenomics; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; mortality; new therapeutic target; novel strategies; novel therapeutic intervention; programs; promoter; resistance gene; response; small molecule; therapeutic biomarker; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecological malignancy. Although majority of the cancer cases are initially sensitive to platinum-based chemotherapy, most patients eventually develop recurrence and succumb to chemoresistant disease. Our lack of understanding of the key drivers that lead to the resistant state poses a critical roadblock that impedes therapeutic progress in the field. The long-term goal of our research is to understand the chromatin and transcriptional regulatory networks that allow cells to adapt to new environmental or developmental cues. The overall objective of this study, which is the next step toward attainment of our long-term goal, is to identify the major regulatory networks that allow ovarian cancer cells to survive chemotherapy. This knowledge will identify improved and effective therapeutics options. To achieve this, we started with epigenome mapping and transcriptome analysis of an in vitro system in which we employed chemonaïve, chemoresistant, and resensitized isogenic cells. Integrative analysis of expression profiles (RNA-Seq) and epigenomic features of promoter and enhancer elements (H3K27ac ChIP-Seq), identified large number of typical enhancers and a subset of “super enhancers” that are specifically activated in resistant cells. Notably, pharmacological disruption of super enhancers by a small molecule epigenetic inhibitor confers cisplatin sensitivity to previously resistant cells in vitro and inhibits in vivo tumor growth in a xenograft model of resistant cells. Super enhancers tend to regulate the expression of master regulators of a given cellular state (1, 2). Among the top target genes of the resistant specific super enhancers (RSSE) were multiple transcription factors, whose depletion with CRISPR mediated knock significantly sensitized the resistant cells to chemotherapy. These preliminary data led to the central hypothesis that aberrant transcriptional program in chemoresistant cells is driven by a set of genes whose expression is regulated by distal enhancers that can be pharmacologically targeted. This proposal will determine the therapeutic efficacy of enhancer targeting to overcome chemoresistance (Aim 1), identify the in vivo dynamics of chemotherapy-induced aberrant enhancer activation (Aim 2), and delineate the core TFs that drives the chemoresistance process (Aim 3). The rationale is to identify and target the major drivers of chemoresistant cellular state genetically, epigenetically, and pharmacologically. The results will allow us to better understand the biology of chemoresistance, and enable development of new and innovative treatment approaches that are applicable to other cancers.

项目概要/摘要 尽管大多数癌症病例是卵巢癌，但它是最致命的妇科恶性肿瘤。 最初对铂类化疗敏感，大多数患者最终出现复发并 我们对导致耐药性疾病的关键驱动因素缺乏了解。 耐药状态是阻碍该领域长期治疗进展的关键障碍。 我们研究的目标是了解染色质和转录调控网络 细胞适应新的环境或发育线索这项研究的总体目标是。 实现我们长期目标的下一步是确定主要的监管网络 让卵巢癌细胞在化疗中存活下来，这一知识将确定改进和有效的方法。 治疗选择。 为了实现这一目标，我们从体外的表观基因组图谱和转录组分析开始 我们采用化疗、化疗和再敏化等基因细胞的系统。 启动子和增强子的表达谱（RNA-Seq）和表观基因组特征分析 元素（H3K27ac ChIP-Seq），鉴定出大量典型增强子和“超级增强子”的子集 增强剂”在耐药细胞中被特异性激活，特别是，超级药理破坏。 小分子表观遗传抑制剂的增强剂赋予顺铂对先前耐药的敏感性 体外细胞并抑制超级增强剂异种移植模型中的体内肿瘤生长。 倾向于调节给定细胞状态的主调节因子的表达 (1, 2)。 抗性特异性超级增强子（RSSE）的靶基因是多种转录因子， CRISPR 介导的敲除使抗性细胞显着敏感 化疗。 这些初步数据得出了一个中心假设，即 aber 转录程序在 化疗耐药细胞由一组基因驱动，这些基因的表达受远端增强子的调节， 该提案将确定增强剂的治疗效果。 靶向克服化疗耐药性（目标 1），确定化疗诱导的体内动力学 异常增强子激活（目标 2），并描绘驱动化学耐药性的核心 TF 过程（目标 3）。其基本原理是确定并针对化学耐药细胞状态的主要驱动因素。 遗传学、表观遗传学和药理学的结果将使我们更好地理解。 化学耐药性的生物学，并能够开发新的和创新的治疗方法 适用于其他癌症。