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

• 批准号: 9980173
• 负责人: Derrick Lee
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/9980173
• 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; 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; cell growth; chromosome conformation capture; cohort; design; drug development; experimental study; improved; in vivo; insight; knock-down; mRNA Expression; new therapeutic target; next generation; novel; novel therapeutics; outcome forecast; p38 Mitogen Activated Protein Kinase; promoter; protein protein interaction; response; self-renewal; small hairpin RNA; stem; stem cell proliferation; stem cells; temozolomide; therapeutic target; transcription factor; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression; tumorigenesis; tumorigenic

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

项目摘要 虽然癌症传统上被视为完全基于遗传畸变的疾病过程， 越来越多的证据表明，表观遗传学改变有助于发病和进展 多种类型的癌症。一种新兴的癌症表观遗传驱动因素是超增强剂，它被定义为 在基因组附近的典型增强子簇。超级增强剂的重要性是由其 通过调节谱系特异性基因表达来决定细胞状态和身份， 与疾病相关的遗传变异的富集。从癌细胞中鉴定出的超级增强剂识别肿瘤- 与多种癌症类型相关的基因，包括多发性脑肿瘤。由于密切的联系 在超增强子结构和生物学功能之间，疾病特异性超增强子的改变可能 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， 尽管进行了深入的研究。胶质母细胞瘤预后不良的一个主要原因是 是干细胞样癌细胞的存在，通常被称为癌症干细胞。癌症干细胞在功能上 通过它们在移植时自我更新、分化和形成肿瘤的能力来定义。癌症干细胞 有助于抵抗放疗和化疗，以及维持肿瘤异质性， 血管生成因此，肿瘤干细胞已成为设计新型治疗药物的重要靶点。 战略布局为了更好地了解神经胶质瘤干细胞身份的关键调控因子， 鉴定了在神经胶质瘤干细胞中表观遗传学上调的基因， 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 与患者预后不良相关的超增强剂。靶向与 超增强剂显示了活力的丧失，表明了这一发现努力的潜在价值。这种方法 揭示了一组潜在的超级增强子相关基因，我建议进一步研究。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， 转录因子占有率和超级增强子结构。第二个目标将确定 胶质瘤细胞存活、自我更新能力和肿瘤形成中的超增强相关基因， 体外和体内环境。第三个目标将阐明这些基因促进细胞凋亡的分子机制。 肿瘤发生这些方法将导致更好地理解表观遗传特征， 神经胶质瘤干细胞状态和新疗法的发展