Targeting Kif11 to Treat Glioblastoma Invasion and Proliferation

靶向 Kif11 治疗胶质母细胞瘤侵袭和增殖

• 批准号: 10083766
• 负责人: Peter Canoll
• 金额: $ 56.06万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083766
• 关键词: ABCB1 gene; ABCG2 gene; Address; Binding; Brain; Brain Neoplasms; CRISPR/Cas technology; Cell Transplantation; Cells; Centrosome; Chronic; Clinical; Convection; Data; Disease; Drug Delivery Systems; Drug Exposure; Drug resistance; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family; Gene Expression Profile; Generations; Genes; Genetic Transcription; Glioblastoma; Glioma; Impairment; Invaded; Kinesin; Measures; Mediating; Methods; Microtubules; Mitosis; Mitotic; Mitotic spindle; Molecular Motors; Mus; Mutation; Neuraxis; Patients; Pharmaceutical Preparations; Phenotype; Play; Point Mutation; Pre-Clinical Model; Proliferating; Pump; Relapse; Resistance; Resistance development; Role; Testing; Therapeutic; Transcription Alteration; Tumor Cell Invasion; Up-Regulation; base; cancer cell; cell killing; cell motility; drug development; drug sensitivity; effective therapy; efficacy evaluation; efflux pump; experience; experimental study; improved; improved outcome; inhibitor/antagonist; malignant phenotype; mouse model; neoplastic cell; novel therapeutics; overexpression; premature; prevent; response; single-cell RNA sequencing; targeted treatment; transcriptomics; translational study; tumor

PROJECT DESCRIPTION The ability of glioblastomas to proliferate in an uncontrollable manner and disperse widely within normal brain define the malignant phenotype and make this disease uniformly lethal. We have identified an enzyme that is essential for both glioblastoma invasion and proliferation—Kif11. This enzyme is a molecular motor of the mitotic kinesin family, and is needed both for formation of the mitotic spindle during mitosis as well as for microtubule-based cell motility. Furthermore, it can be inhibited with clinically available drugs that we have shown significantly prolong survival in mouse models of glioblastoma. In this application, we will examine how to optimize the delivery of these drugs to the central nervous system and to identify and overcome the mechanisms tumor cells use to develop resistance to them. Results from these translational studies will be vital to our ongoing efforts at developing Kif11 inhibitors as new and effective therapies for the treatment of glioblastoma.

项目描述 胶质母细胞瘤以不可控制的方式增殖并在正常脑内广泛分散的能力 定义恶性表型并使这种疾病一致致命。我们发现了一种酶 对胶质母细胞瘤的侵袭和增殖至关重要-Kif 11。这种酶是一种分子马达， 有丝分裂驱动蛋白家族，并且在有丝分裂期间形成有丝分裂纺锤体以及 基于微管的细胞运动。此外，它可以被抑制与临床可用的药物，我们有 在胶质母细胞瘤小鼠模型中显示出显著延长的存活。在这个应用程序中，我们将研究如何 以优化这些药物向中枢神经系统的递送，并识别和克服 肿瘤细胞用来产生耐药性的机制。这些转化研究的结果将 这对于我们正在努力开发Kif 11抑制剂作为治疗以下疾病的新的有效疗法至关重要： 胶质母细胞瘤