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: 8558924
• 负责人: Jeongwu Lee
• 金额: $ 26.81万
• 依托单位: OHIO STATE UNIVERSITY
• 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/8558924
• 关键词: Affect; Binding; Biochemical; Biological; Brain; Brain Neoplasms; Caring; Cell Survival; Cells; Cellular biology; Characteristics; Clinical; Data; Development; Embryo; Excision; Exhibits; Genes; Genetic; Glioblastoma; Glioma; Glomerular basement membrane antibody; Goals; Growth; Histones; 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; Patients; Phosphorylation; Phosphotransferases; Point Mutation; Process; 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; human EZH2 protein; improved; in vivo; inhibitor/antagonist; kinase inhibitor; mutant; novel; novel therapeutic intervention; novel therapeutics; palliation; palliative; prevent; public health relevance; radiation resistance; response; self-renewal; small molecule; standard care; stem; 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。目前的标准护理疗法仅提供姑息治疗，这表明迫切需要开发更有效的治疗选择。 GBM 在肿瘤内显示出分化状态的层次结构，类似于正常的大脑发育 流程。启动和维持神经胶质瘤的分子信号通常与参与干细胞发育的分子信号重叠，事实上，越来越多的证据表明，GBM 干细胞样细胞 (GSC) 有助于肿瘤增殖、复发以及与这些病变相关的最终生命损失。然而，调节 GSC 存活和治疗耐药性的分子机制仍知之甚少，这阻碍了开发预防 GBM 生长和复发的有效疗法的努力。我们最近的研究和初步数据发现了一种新的分子信号级联，可以控制 GSC 的存活、增殖和治疗耐药性。该途径涉及有丝分裂激酶 MELK、甲基转移酶 EZH2 和致癌转录因子 STAT3。重要的是，该通路的失调会加速 GSC 生长并促进 GBM 恶性肿瘤，并且与患者不良预后密切相关。该项目将探讨 MELK-EZH2-STAT3 通路在 GSC 自我更新、存活、GBM 进展和辐射抗性中的作用。我们的数据强烈表明，通过靶向上游效应器 MELK 抑制 MELK-EZH2-STAT3 信号轴可能具有深远的临床意义，因为它可以同时阻断多个致癌信号通路，所有这些都是众所周知的治疗靶点。为了实现这一目标，我们开发了一种小分子 MELK 抑制剂，可以降低体内 GSC 存活率和肿瘤生长。我们预计这项研究将为 GSC 生物学提供一个新的范式，并提供一种针对 GSC 关键调节因子的新治疗方法，这可能会转化为改进的疗法。