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:
- 金额:$ 41.39万
- 依托单位:
- 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:
- 关键词:Automobile DrivingBiologyCell LineCellsChIP-seqChemoresistanceChromatinCisplatinClinicalClustered Regularly Interspaced Short Palindromic RepeatsCuesDataDevelopmentDiseaseDistalEnhancersEpigenetic ProcessGene ExpressionGene Expression ProfileGene TargetingGenesGeneticGenetic Enhancer ElementGenetic TranscriptionGenomeGenomic SegmentGoalsIn VitroKnock-outKnowledgeLeadMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryMapsMediatingOutcomeOvarianPatientsPharmacologyPhenotypePlatinumProcessRecurrenceRegulationResearchResistanceRoleSamplingSerousSiteSystemTestingTherapeuticTimeTreatment EfficacyWorkXenograft Modelbasecancer cellchemotherapyclinically relevantcombinatorialepigenomeepigenomicsimprovedin vivoin vivo Modelinhibitor/antagonistinnovationmortalitynew therapeutic targetnovel strategiesnovel therapeutic interventionpatient derived xenograft modelprogramspromoterresistance generesponsesmall moleculetargeted biomarkertherapeutically effectivetranscription factortranscriptometranscriptome sequencingtumortumor 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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool.
- DOI:10.1016/j.jmb.2018.05.044
- 发表时间:2019-01-04
- 期刊:
- 影响因子:5.6
- 作者:Brokowski C;Adli M
- 通讯作者:Adli M
The CRISPR tool kit for genome editing and beyond.
- DOI:10.1038/s41467-018-04252-2
- 发表时间:2018-05-15
- 期刊:
- 影响因子:16.6
- 作者:Adli M
- 通讯作者:Adli M
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Mazhar Adli其他文献
Mazhar Adli的其他文献
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{{ truncateString('Mazhar Adli', 18)}}的其他基金
Chemo-mediated transcriptional reprogramming in ovarian cancer
卵巢癌中化疗介导的转录重编程
- 批准号:
10346704 - 财政年份:2022
- 资助金额:
$ 41.39万 - 项目类别:
Molecular and cellular characterization of essential human genes.
人类必需基因的分子和细胞特征。
- 批准号:
10708906 - 财政年份:2022
- 资助金额:
$ 41.39万 - 项目类别:
Chemo-mediated transcriptional reprogramming in ovarian cancer
卵巢癌中化疗介导的转录重编程
- 批准号:
10709477 - 财政年份:2022
- 资助金额:
$ 41.39万 - 项目类别:
Molecular and cellular characterization of essential human genes.
人类必需基因的分子和细胞特征。
- 批准号:
10517781 - 财政年份:2022
- 资助金额:
$ 41.39万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 41.39万 - 项目类别:
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