Comprehensive Identification of bivalent promoters in Brain Tumor Stem Cells

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是脑癌中最恶性的形式，并且仍然是所有人类癌症中最具侵袭性的形式之一，尽管采用多种治疗方法，中位生存期仅为一年多。GBM已被证明含有驱动肿瘤生长的癌症干细胞。这一发现导致了利用肿瘤干细胞特性和脆弱性开发有效疗法的范式转变。清楚地了解有助于癌症干细胞分化和增殖的早期表观遗传事件对于制定针对它们的药理学策略至关重要。在这一建议中，我们的目标是利用高通量标签测序来阐明脑肿瘤干细胞中易受表观遗传畸变影响的基因组区域。这些数据将用于了解这些畸变如何导致基因表达和其他调控胶质母细胞瘤发生和发病的基因组元件的失调。这些研究将具有双重潜在影响：a)为胶质瘤形成机制提供新的见解；b)为胶质瘤的合理治疗干预的发展提供敏感和强大的靶点。公共卫生相关性：多形性胶质母细胞瘤患者面临着一种致命的疾病，治疗方案有限。识别脑肿瘤干细胞中易受表观遗传畸变影响的基因组区域，为开发侵袭性和复发性胶质母细胞瘤的有效治疗方法提供了巨大的希望。启动子甲基化模式和关键基因表达水平的变化可能对成功开发有效治疗具有诊断、治疗或预后意义。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most malignant form of brain cancer and remains one of the most aggressive forms of all human cancers with a median survival of just over one year despite multi modality therapy. GBM has been shown to contain cancer stem cells that are drive tumor growth. This finding has led to paradigm shift in developing effective therapies by exploiting tumor stem cell properties and vulnerabilities. A clear understanding of early epigenetic events that contribute to cancer stem cell differentiation and proliferation will be essential to develop pharmacologic strategies to target them. In this proposal, we aim to elucidate genomic regions that are susceptible for epigenetic aberrations in brain tumor stem cells using high throughput tag sequencing. This data will be used to learn how these aberrations lead to deregulation of gene expression and other genomic elements that orchestrate glioblastoma tumorigenesis and pathogenesis. These studies will have a two fold potential impact: a) provide new insights into mechanisms that contribute to gliomagenesis and b) provide sensitive and robust targets for development of rational therapeutic intervention of glioblastoma. PUBLIC HEALTH RELEVANCE: Patients with glioblastoma multiforme face a deadly disease with limited treatment options. Identification of genomic regions susceptible to epigenetic aberrations in brain tumor stem cells holds a great promise for developing effective therapies for aggressive and recurrent glioblastoma. The changes in promoter methylation patterns and the expression level of key genes may have diagnostic, therapeutic or prognostic significance for the successful development of effective treatment.