Targeting MELK-mediated EZH2 signaling in glioma stem cells

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是一种毁灭性的脑癌，平均生存期只有14.6个月。目前的标准治疗只能提供缓解，这表明迫切需要开发更有效的治疗方案。基底膜显示肿瘤内分化状态的等级，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，事实上，越来越多的证据表明，GBM干细胞(GSCs)有助于肿瘤的增殖、复发和最终与这些病变相关的生命损失。然而，调控GSC存活和治疗耐药性的分子机制仍然知之甚少，这阻碍了开发有效的治疗方法来防止GBM生长和复发的努力。我们最近的研究和初步数据发现了一个新的分子信号级联，它可能控制GSCs的生存、增殖和治疗耐药。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，这一通路的失调加速了GSC的生长，促进了GBM的恶性，并与不良的患者预后密切相关。这个项目将询问这个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。我们的数据有力地表明，通过靶向上游效应因子Melk来抑制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条致癌信号通路，所有这些都是众所周知的治疗靶点。为了达到这个目标，我们开发了一种小分子的Melk抑制剂，可以降低GSC的存活和体内肿瘤的生长。我们预计，这项研究将为GSC生物学提供一个新的范式，并为靶向GSC的关键调控因子提供一种新的治疗方法，这可能导致转化为改进的治疗方法。

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.