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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

基本信息

批准号：
10166791
负责人：
Mazhar Adli
金额：
$ 41.39万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10166791
关键词：
Automobile Driving Biology Cell Line Cells ChIP-seq Chemoresistance Chromatin Cisplatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cues Data Development Disease Distal Enhancers Epigenetic Process Gene Expression Gene Expression Profile 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 Outcome Ovarian Patients Pharmacology Phenotype Platinum Process Recurrence Regulation Research Resistance Role Sampling Serous Site System Testing Therapeutic Time Treatment Efficacy Work Xenograft Model 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 patient derived xenograft model programs promoter resistance gene response small molecule targeted biomarker therapeutically effective transcription factor transcriptome transcriptome sequencing tumor tumor growth

项目摘要

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.

项目摘要/摘要卵巢癌是最致命的妇科恶性肿瘤。尽管大多数癌症病例都是最初对铂类化疗敏感，大多数患者最终发展为复发和死于抗药性疾病。我们对导致经济衰退的关键驱动因素缺乏了解耐药状态构成了阻碍该领域治疗进展的关键障碍。长期的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为了实现我们的长期目标，下一步是确定主要的监管网络，允许卵巢癌细胞在化疗后存活。这些知识将确定改进的和有效的治疗选择。为了实现这一点，我们从表观基因组图谱和体外转录组学分析开始。我们使用化疗、耐化疗和再敏化等基因细胞的系统。集成式启动子和增强子的表达谱(RNA-Seq)和表观基因组学特征分析 Elements(H3K27ac CHIP-SEQ)，确定了大量典型的增强剂和一个子集在耐药细胞中被特异性激活的“增强剂”。值得注意的是，SERVER的药理破坏小分子表观遗传抑制剂的增强剂增强顺铂对先前耐药的敏感性并在耐药细胞异种移植模型中抑制体内肿瘤生长。超级增强剂倾向于调节给定细胞状态的主调节器的表达(1，2)。名列前茅抗性特异性超级增强子(RSSE)的靶基因是多个转录因子， CRISPR介导的敲击使其耗尽，使耐药细胞对化疗。这些初步数据导致了中心假说，异常转录程序在化疗耐药细胞是由一组基因驱动的，这些基因的表达受到远端增强子的调节，这些基因在药理上是有靶向性的。这项建议将决定增强剂的治疗效果。以克服化疗耐药为目标(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)，并描绘驱动化疗耐药的核心转录因子进程(目标3)。其基本原理是识别和定位化疗耐药细胞状态的主要驱动因素从遗传学、表观遗传学和药理学上讲。结果将使我们更好地理解化疗耐药的生物学，并使新的创新治疗方法的开发成为可能也适用于其他癌症。