Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors

描述（由申请人提供）：恶性胶质瘤弥漫性浸润周围大脑的能力使其无法通过手术切除，肿瘤扩散到关键的大脑区域导致肿瘤复发，并最终导致与这些病变相关的生命损失。然而，调节胶质瘤细胞运动和侵袭的细胞内机制仍然知之甚少，这阻碍了开发防止胶质瘤侵袭的治疗方法的努力。我们已经确定了一种新的细胞内通路，它控制恶性胶质瘤细胞的细胞骨架组织、迁移和侵袭，并且在胶质母细胞瘤中失调。该途径涉及细胞周期蛋白依赖性激酶相关磷酸酶、KAP（在胶质母细胞瘤中异常剪接）、Rho激酶和Cdc2激酶。重要的是，在体外和小鼠大脑中，使用Cdc2激酶抑制剂的小分子抑制该途径可减少CD133+胶质瘤来源的干细胞样细胞的迁移和侵袭。此外，该通路的失调定义了与不良患者预后相关的人类胶质母细胞瘤亚群。本项目将研究KAP/ROCK/Cdc2侵袭途径在人类CD133+胶质母细胞瘤衍生干细胞中的下游效应机制。此外，我们将研究Cdc2激酶的小分子抑制对胶质母细胞瘤扩散和体内总体存活的影响，方法是将人胶质瘤来源的干细胞颅内移植到小鼠大脑中。几种小分子Cdc2抑制剂目前正在用于其他目的的人体临床试验中，因此可能具有在临床试验中用于预防恶性胶质瘤扩散的治疗潜力。

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.