Targeting brain tumor initiating cell-specific super-enhancer associated genes to treat glioblastoma

靶向脑肿瘤启动细胞特异性超级增强子相关基因治疗胶质母细胞瘤

基本信息

批准号：
10176425
负责人：
Derrick Lee
金额：
$ 4.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176425
关键词：
Binding Binding Sites Biological Assay Biological Process Brain Neoplasms Catalytic Domain Cell Maintenance Cell Proliferation Cell Survival Cells ChIP-seq Chemotherapy and/or radiation Chromatin Co-Immunoprecipitations Dependence Development Disease Disease remission Enhancers Epidermal Growth Factor Receptor Epigenetic Process Excision Future Gene Expression Genes Genetic Genetic Enhancer Element Genetic Transcription Genetic Variation Genomics Glioblastoma Glioma Growth Histones Impairment In Vitro Lysine MAP Kinase Gene Maintenance Malignant Neoplasms Malignant neoplasm of brain Mediating Modality Molecular Oncogenes Oncogenic Operative Surgical Procedures Pathogenesis Pathway interactions Patients Population Primary Brain Neoplasms Process Prognosis Protein phosphatase Proteins Proto-Oncogene Proteins c-akt Quality of life Radiation therapy Regulation Research Resistance Role Signal Transduction Stretching Structure Therapeutic Time Transcriptional Regulation Transplantation Tumor Angiogenesis Tumorigenicity base cancer cell cancer stem cell cancer type chromosome conformation capture cohort design drug development experimental study improved in vivo insight knock-down mRNA Expression new therapeutic target next generation novel novel therapeutic intervention novel therapeutics p38 Mitogen Activated Protein Kinase promoter protein protein interaction response self-renewal small hairpin RNA stem stem cell growth stem cell proliferation stem cells temozolomide therapeutic target transcription factor tumor tumor growth tumor heterogeneity tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY While cancer has traditionally been viewed as a disease process based exclusively on genetic aberrations, increasing evidence has demonstrated that epigenetic alterations contribute to the pathogenesis and progression of many types of cancer. One emerging epigenetic driver of cancer is the superenhancer, which is defined as a cluster of typical enhancers in close genomic proximity. The significance of superenhancers is supported by their roles in determining cell state and identity through regulation of lineage-specific gene expression, with enrichment in disease-associated genetic variation. Superenhancers identified from cancer cells identify tumor- associated genes in a number of cancer types, including multiple brain tumors. Due to the close association between superenhancer structure and biological function, alterations in disease-specific superenhancers may reveal insights into the molecular mechanisms of disease pathogenesis. Glioblastoma is the most common and most aggressive primary brain tumor, with poor responses to all therapeutic modalities despite intensive research. One major contributor to the poor prognosis of glioblastoma is the presence of stem-like cancer cells, often called cancer stem cells. Cancer stem cells are functionally defined by their abilities to self-renew, differentiate, and form tumors upon transplantation. Cancer stem cells contribute to resistance to radiation and chemotherapy, as well as maintenance of tumor heterogeneity and angiogenesis. Thus, cancer stem cells have become an important target for the design of novel therapeutic strategies. To better understand key regulators of glioma stem cell identity, an original super-enhancer screen identified genes that are epigenetically upregulated in glioma stem cells and for which elevated expression is associated with poor patient prognosis. Leveraging chromatin landscape analysis of patient-derived glioblastoma stem cells, I identified putative superenhancers that are associated with poor patient prognosis. Targeting the genes associated with the superenhancers revealed a loss of viability, suggesting potential value in this discovery effort. This approach revealed a cohort of potential super-enhancer associated genes that I propose for further study. I will investigate the transcription factor network that regulates the expression of these genes including enhancer elements, transcription factor occupancy, and super-enhancer structure. The second aim will define the role of the superenhancer-associated genes in glioma cell survival, self-renewal capacity, and tumor formation in both in vitro and in vivo settings. The third aim will elucidate the molecular mechanism by which these genes promote tumorigenesis. These approaches will lead to a greater understanding of the epigenetic features that define the glioma stem cell state and inform the development of novel therapeutics

项目概要虽然癌症传统上被视为一种完全基于遗传畸变的疾病过程，越来越多的证据表明表观遗传改变有助于发病机制和进展许多类型的癌症。一种新兴的癌症表观遗传驱动因素是超级增强子，它被定义为一种基因组附近的典型增强子簇。超级增强剂的重要性得到了它们的支持通过调节谱系特异性基因表达来确定细胞状态和身份的作用，疾病相关遗传变异的丰富。从癌细胞中鉴定出的超级增强剂可识别肿瘤多种癌症类型（包括多种脑肿瘤）的相关基因。由于密切的联系在超级增强子结构和生物功能之间，疾病特异性超级增强子的改变可能揭示疾病发病机制的分子机制。胶质母细胞瘤是最常见和最具侵袭性的原发性脑肿瘤，对所有肿瘤的反应都很差尽管进行了深入的研究，但治疗方式仍然存在。胶质母细胞瘤预后不良的一个主要原因是干细胞样癌细胞的存在，通常称为癌症干细胞。癌症干细胞在功能上定义为它们在移植后自我更新、分化和形成肿瘤的能力。癌症干细胞有助于抵抗放疗和化疗，以及维持肿瘤异质性和血管生成。因此，癌症干细胞已成为设计新型治疗药物的重要靶点。策略。为了更好地了解神经胶质瘤干细胞身份的关键调节因子，原创的超级增强子筛选鉴定出在神经胶质瘤干细胞中表观遗传上调的基因，并且这些基因的表达升高与患者预后不良有关。利用患者来源的胶质母细胞瘤干细胞的染色质景观分析，我确定了假定的与患者不良预后相关的超级增强剂。靶向相关基因超级增强剂显示出活力的丧失，表明这一发现工作的潜在价值。这种做法揭示了一组潜在的超级增强子相关基因，我建议对其进行进一步研究。我会调查调节这些基因表达的转录因子网络，包括增强子元件，转录因子占据和超增强子结构。第二个目标将定义超级增强子相关基因在神经胶质瘤细胞存活、自我更新能力和肿瘤形成中的作用体外和体内设置。第三个目标将阐明这些基因促进的分子机制肿瘤发生。这些方法将有助于更好地理解定义基因的表观遗传特征。神经胶质瘤干细胞状态并为新疗法的开发提供信息