Targeting MELK-mediated EZH2 signaling in glioma stem cells

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。目前的标准治疗仅提供缓解，这表明迫切需要开发更有效的治疗方案。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，并且确实积累的证据表明GBM干细胞样细胞（GSC）有助于肿瘤增殖、复发和与这些病变相关的最终生命丧失。然而，调节GSC存活和治疗抗性的分子机制仍然知之甚少，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，可能控制GSC的存活，增殖和治疗抗性。该途径涉及有丝分裂激酶MELK、甲基转移酶EZH 2和致癌转录因子STAT 3。重要的是，该途径的失调加速GSC生长并促进GBM恶性，并且与不良患者结局密切相关。该项目将探讨MELK-EZH 2-STAT 3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，通过靶向上游效应物MELK来抑制MELK-EZH 2-STAT 3信号传导轴可能具有深远的临床意义，因为它可以同时阻断多种致癌信号传导途径，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的存活率和肿瘤生长。我们预计，这项研究将产生一个新的范式GSC生物学和一种新的治疗方法，以目标的关键调控GSC，这可能会导致翻译成改进的疗法。

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.