Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors

描述(申请人提供)：恶性胶质瘤扩散到周围大脑的能力使它们无法通过手术切除治愈，肿瘤扩散到关键脑区导致肿瘤复发和最终与这些病变相关的生命损失。然而，调控胶质瘤细胞运动和侵袭的细胞内机制仍然知之甚少，这阻碍了开发预防胶质瘤侵袭的治疗方法的努力。我们已经发现了一种新的细胞内途径，它控制着恶性胶质瘤细胞的细胞骨架组织、迁移和侵袭，这在胶质母细胞瘤中是不受调控的。该通路涉及细胞周期蛋白依赖的激酶相关的磷酸酶、KAP(在胶质母细胞瘤中异常剪接)、Rho激酶和CDc2激酶。重要的是，使用CDC2激酶抑制剂抑制这一途径的小分子减少了CD133胶质瘤干细胞在体外和小鼠脑内的迁移和侵袭。此外，这一途径的失调定义了与不良患者预后相关的人类胶质母细胞瘤的亚群。本项目将研究这种KAP/ROCK/CDC2侵袭途径在人CD133胶质母细胞瘤样干细胞中的下游效应机制。此外，我们将通过将人脑胶质瘤干细胞脑内移植到小鼠脑内来检测小分子抑制CDc2激酶对胶质母细胞瘤体内扩散和总体存活的影响。几种小分子Cdc2抑制剂目前正用于人类临床试验，用于其他目的，因此可能具有治疗潜力，用于临床试验，以防止恶性胶质瘤扩散。

DESCRIPTION (provided by applicant): The ability of malignant gliomas to diffusely infiltrate the surrounding brain has rendered them incurable by surgical resection, and the spread of tumor into critical brain areas contributes to tumor recurrence and the eventual loss of life associated with these lesions. However, the intracellular mechanisms regulating glioma cell motility and invasion remain poorly understood, and this has hampered efforts to develop therapies that prevent glioma invasion. We have identified a novel intracellular pathway that controls the cytoskeletal organization, migration and invasion of malignant glioma cells, and that is dysregulated in glioblastoma. This pathway involves the cyclin-dependent kinase-associated phosphatase, KAP (which is aberrantly spliced in glioblastoma), Rho kinase and Cdc2 kinase. Importantly, small molecule inhibition of this pathway using a Cdc2 kinase inhibitor decreases the migration and invasion of CD133+ glioma-derived stem-like cells in vitro and in the mouse brain. Moreover, dysregulation of this pathway defines a subpopulation of human glioblastomas associated with poor patient outcome. This project will examine the downstream effector mechanisms of this KAP/ROCK/Cdc2 invasion pathway in human CD133+ glioblastoma- derived stem-like cells. In addition, we will examine the effects of small molecule inhibition of Cdc2 kinase on glioblastoma dispersal and overall survival in vivo using intracranial transplantation of human glioma-derived stem-like cells into the mouse brain. Several small molecule Cdc2 inhibitors are currently being used in human clinical trials for other purposes, and may thus have therapeutic potential for use in clinical trials to prevent malignant glioma dispersal.