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）：恶性神经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治愈，并且肿瘤扩散到关键大脑区域会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，调节神经胶质瘤细胞运动和侵袭的细胞内机制仍然知之甚少，这阻碍了开发预防神经胶质瘤侵袭的疗法的努力。我们发现了一种新的细胞内途径，可以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。该通路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，使用 Cdc2 激酶抑制剂对该通路进行小分子抑制可减少体外和小鼠大脑中 CD133+ 神经胶质瘤来源的干细胞的迁移和侵袭。此外，该通路的失调定义了与患者预后不良相关的人类胶质母细胞瘤亚群。该项目将研究人 CD133+ 胶质母细胞瘤来源的干细胞中 KAP/ROCK/Cdc2 入侵途径的下游效应机制。此外，我们将通过将人胶质瘤来源的干细胞颅内移植到小鼠大脑中，检查小分子抑制 Cdc2 激酶对胶质母细胞瘤扩散和体内总体生存的影响。目前，几种小分子 Cdc2 抑制剂正用于其他目的的人体临床试验，因此可能具有用于预防恶性胶质瘤扩散的临床试验的治疗潜力。 公共卫生相关性：调节神经胶质瘤侵袭周围大脑的细胞内机制仍知之甚少。我们发现了一种调节神经胶质瘤迁移的新细胞内途径，涉及细胞周期蛋白依赖性激酶相关磷酸酶、KAP、Rho 激酶和 Cdc2 激酶。该通路的失调定义了与患者预后不良相关的胶质母细胞瘤亚群。该项目将研究人 CD133+ 胶质母细胞瘤来源的干细胞和已建立的胶质瘤细胞系中 KAP/ROCK/Cdc2 入侵途径的下游效应机制。 Cdc2 激酶抑制对胶质母细胞瘤扩散和总体生存的影响也将使用小鼠颅内人胶质瘤移植模型来确定。