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）是脑癌的最恶性形式，并且仍然是所有人类癌症中最具侵袭性的形式之一，尽管进行了多模态治疗，但中位生存期仅超过一年。GBM已被证明含有驱动肿瘤生长的癌症干细胞。这一发现导致了通过利用肿瘤干细胞的特性和脆弱性来开发有效疗法的范式转变。清楚地了解早期表观遗传事件，有助于癌症干细胞分化和增殖将是至关重要的发展药理学策略，以针对他们。在这个建议中，我们的目标是阐明基因组区域，是易感的表观遗传畸变在脑肿瘤干细胞使用高通量标签测序。这些数据将用于了解这些畸变如何导致基因表达和其他基因组元素的失调，协调胶质母细胞瘤的肿瘤发生和发病机制。这些研究将具有双重潜在影响：a）为促进胶质瘤发生的机制提供新的见解，以及B）为开发胶质母细胞瘤的合理治疗干预提供敏感和稳健的靶点。公共卫生相关性：多形性胶质母细胞瘤患者面临着一种治疗选择有限的致命疾病。鉴定脑肿瘤干细胞中易受表观遗传畸变影响的基因组区域对于开发侵袭性和复发性胶质母细胞瘤的有效疗法具有很大的希望。启动子甲基化模式和关键基因表达水平的变化可能对有效治疗的成功开发具有诊断、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.