Targeting MELK-mediated EZH2 signaling in glioma stem cells

靶向神经胶质瘤干细胞中 MELK 介导的 EZH2 信号传导

• 批准号: 9117637
• 负责人: Jeongwu Lee
• 金额: $ 28.91万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117637
• 关键词: Affect; Binding; Biochemical; Biological; Brain; Brain Neoplasms; Cell Survival; Cells; Cellular biology; Characteristics; Clinical; Data; Development; Embryo; Enhancers; Excision; Exhibits; Genes; Genetic; Glioblastoma; Glioma; Glomerular basement membrane antibody; Goals; Growth; Health; Homologous Gene; Individual; Lead; Lesion; Leucine Zippers; Life; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediating; Methylation; Mitotic; Modeling; Molecular; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Phosphotransferases; Point Mutation; Process; Protein Methylation; Protein-Serine-Threonine Kinases; Proteins; Radiation; Radiation therapy; Recurrence; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Stat3 protein; Stem Cell Development; Stem cells; Testing; Therapeutic; Transferase; Translations; Treatment Efficacy; Treatment Protocols; Tumor Stem Cells; arm; base; cell growth; chemotherapy; conventional therapy; effective therapy; gene repression; histone methylation; improved; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; mutant; novel; novel therapeutic intervention; novel therapeutics; palliation; palliative; prevent; radiation resistance; response; self-renewal; small molecule; standard care; standard of care; stem; targeted treatment; therapeutic target; therapy resistant; transcription factor; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a devastating brain cancer with a mean survival of only 14.6 months. Current standard-of-care therapies provide only palliation, indicating an urgent need to develop more effective therapeutic options. GBMs display a hierarchy of differentiation states within the tumor, similar to normal brain development processes. Molecular signals that initiate and maintain gliomas commonly overlap with those involved in stem cell development, and indeed accumulating evidence suggests that GBM stem-like cells (GSCs) contribute to tumor propagation, recurrence and the eventual loss of life associated with these lesions. However, molecular mechanisms that regulate GSC survival and therapy resistance remain poorly understood, and this has hampered efforts to develop effective therapies that prevent GBM growth and recurrence. Our recent studies and preliminary data have discovered a novel molecular signaling cascade that may control the survival, proliferation, and therapy resistance of GSCs. This pathway involves the mitotic kinase MELK, methyl transferase EZH2, and oncogenic transcription factor STAT3. Importantly, dysregulation of this pathway accelerates GSC growth and promotes GBM malignancy, and are tightly associated with poor patient outcome. This project will interrogate the role of this MELK-EZH2-STAT3 pathway in GSC self-renewal, survival, GBM progression, and radiation resistance. Our data strongly indicate that inhibition of the MELK-EZH2-STAT3 signaling axis by targeting the upstream effector MELK may have profound clinical implications since it can simultaneously block multiple oncogenic signaling pathways all of which are the well-known therapeutic targets. Toward this goal, we have developed a small-molecule MELK inhibitor that could decrease GSC survival and tumor growth in vivo. We anticipate that this study will yield a new paradigm for GSC biology and a novel therapeutic approach to target key regulators of GSC, which may lead to the translation into improved therapies.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种毁灭性的脑癌，平均生存期仅为14.6个月。目前的标准治疗只能提供姑息治疗，这表明迫切需要开发更有效的治疗方案。GBMs在肿瘤内表现出分化状态的层次结构，类似于正常的大脑发育