Preventing Glioma Cancer Stem Cell Dispersal Using Cdc2 Kinase Inhibitors

使用 Cdc2 激酶抑制剂预防神经胶质瘤干细胞扩散

• 批准号: 8213710
• 负责人: MARK D JOHNSON
• 金额: $ 35.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213710
• 关键词: Actins; Area; Biological Assay; Brain; Cells; Clinical Trials; Cyclin D1; Cyclin-Dependent Kinase Inhibitor 3; Cyclin-Dependent Kinases; Cytoskeletal Modeling; Dominant-Negative Mutation; Excision; Focal Adhesions; Genetic Transcription; Glioblastoma; Glioma; Human; In Vitro; Lesion; Life; Malignant Glioma; Mediating; Messenger RNA; Microtubules; Modeling; Mus; Myosin Light Chain Kinase; Myosin Light Chains; Operative Surgical Procedures; Outcome; PTK2 gene; Pathway interactions; Patients; Peripheral; Phosphorylation; Phosphotransferases; Play; Proteins; RNA Interference; RNA Splicing; Recurrence; Rho-associated kinase; Role; Small Interfering RNA; Therapeutic; Transplantation; Tumor Suppressor Proteins; caldesmon; cancer stem cell; cell motility; glioma cell line; in vivo; inhibitor/antagonist; kinase inhibitor; migration; novel; overexpression; prevent; public health relevance; research study; small molecule; stem; therapy development; tumor

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. PUBLIC HEALTH RELEVANCE: The intracellular mechanisms regulating glioma invasion of the surrounding brain remain poorly understood. We have identified a novel intracellular pathway that regulates glioma migration and involves the cyclin-dependent kinase-associated phosphatase, KAP, Rho kinase and Cdc2 kinase. Dysregulation of this pathway defines a subpopulation of 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 and in established glioma cell lines. The effect of Cdc2 kinase inhibition on glioblastoma dispersal and overall survival will also be determined using a mouse intracranial human glioma transplantation model.

描述（由申请人提供）：恶性胶质瘤弥漫性浸润周围脑的能力使其无法通过手术切除治愈，并且肿瘤扩散到关键脑区有助于肿瘤复发和与这些病变相关的最终生命损失。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，这阻碍了开发预防胶质瘤侵袭的疗法的努力。我们已经确定了一种新型细胞内途径，该途径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Cdc 2激酶。重要的是，使用Cdc 2激酶抑制剂抑制该途径的小分子降低了体外和小鼠脑中CD 133+神经胶质瘤源性干细胞样细胞的迁移和侵袭。此外，该途径的失调定义了与不良患者结局相关的人类胶质母细胞瘤亚群。本项目将研究人CD 133+胶质母细胞瘤源性干细胞样细胞中KAP/ROCK/Cdc 2侵袭通路的下游效应机制。此外，我们将研究小分子抑制Cdc 2激酶对胶质母细胞瘤扩散和总生存率的影响，在体内使用颅内移植的人胶质瘤源性干细胞样细胞到小鼠脑中。几种小分子Cdc 2抑制剂目前正用于人类临床试验中用于其他目的，因此可能具有用于临床试验以预防恶性胶质瘤扩散的治疗潜力。 公共卫生相关性：调节胶质瘤侵袭周围脑的细胞内机制仍然知之甚少。我们已经确定了一种新的细胞内途径，调节胶质瘤的迁移，并涉及细胞周期蛋白依赖性激酶相关磷酸酶，KAP，Rho激酶和Cdc 2激酶。该通路的失调定义了与不良患者结局相关的胶质母细胞瘤亚群。该项目将研究这种KAP/ROCK/Cdc 2侵袭途径在人CD 133+胶质母细胞瘤源性干细胞样细胞和已建立的胶质瘤细胞系中的下游效应机制。Cdc 2激酶抑制对胶质母细胞瘤扩散和总存活的影响也将使用小鼠颅内人胶质瘤移植模型来确定。