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）：恶性神经胶质瘤扩散浸润周围大脑的能力使它们无法通过手术切除使它们无法治愈，并且肿瘤进入关键大脑区域的扩散会导致肿瘤复发，并导致与这些病变相关的生命丧失。然而，调节神经胶质瘤细胞运动和侵袭的细胞内机制仍然鲜为人知，这阻碍了开发防止神经胶质瘤侵袭的疗法的努力。我们已经确定了一种新型的细胞内途径，该途径控制了恶性神经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激酶抑制剂对该途径的小分子抑制降低了CD133+神经胶质瘤衍生的样干细胞在体外和小鼠脑中的迁移和侵袭。此外，该途径的失调定义了与患者不良结局相关的人胶质母细胞瘤的亚群。该项目将检查人CD133+胶质母细胞瘤衍生的类样细胞中该KAP/岩石/CDC2入侵途径的下游效应器机制。此外，我们将利用人神经胶质瘤衍生的类样细胞进入小鼠大脑的颅内移植来检查小分子抑制Cdc2激酶对体内胶质母细胞瘤分散和总生存的影响。目前，用于其他目的的人类临床试验中使用了几种小分子CDC2抑制剂，因此可能具有用于预防恶性神经胶质瘤分散体的临床试验中使用的治疗潜力。 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然很少了解。我们已经确定了一种调节神经胶质瘤迁移的新型细胞内途径，并涉及细胞周期蛋白依赖性激酶相关的磷酸酶，KAP，RHO激酶和CDC2激酶。该途径的失调定义了与差的患者预后相关的胶质母细胞瘤的亚群。该项目将检查人类CD133+胶质母细胞瘤衍生的类样的干细胞和已建立的神经胶质瘤细胞系中该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分散和总生存期的影响也将使用小鼠颅内人神经胶质瘤移植模型确定。