Aurora-A is a novel therapeutic target in glioblastoma

Aurora-A 是胶质母细胞瘤的新治疗靶点

基本信息

批准号：
8915765
负责人：
NORMAN LEHMAN
金额：
$ 35.94万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915765
关键词：
Adult Angiogenesis Inhibitors Angiogenic Factor Animal Model Animals Apoptosis Applications Grants Biochemical Pathway Biological Biological Assay Bos taurus PARP protein Brain Brain Neoplasms CDC2 Protein Kinase Carboplatin Caspase Cell Culture Techniques Cell physiology Cells Clinical Clinical Trials Combined Modality Therapy Cultured Cells Cyclin B Cytokinesis DNA Data Diagnosis Differentiation Antigens Drug Targeting Effectiveness Endothelial Cells Exhibits Feulgen stain Flow Cytometry Galactosidase Genome Stability Genomic Instability Glial Fibrillary Acidic Protein Glioblastoma Glioma Glycogen Synthase Kinase 3 Goals Health Human Hypoxia In Situ Nick-End Labeling In Vitro Laboratories Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measurable Mediating Messenger RNA MicroRNAs Mitosis Mitotic Mus NF-kappa B Oncogenic Patient Monitoring Patients Perfusion Pharmaceutical Preparations Phosphorylation Phosphotransferases Ploidies Protein Family Protein-Serine-Threonine Kinases Proteins RNA Interference Radiation Recurrent tumor Regulation Resistance Role Sampling Signal Pathway Signal Transduction Signaling Protein Slice Staining method Stains Subfamily lentivirinae Taxane Compound Testing Time Tumor Angiogenesis Tumor Cell Invasion Vascular Endothelial Growth Factors Vascular Proliferation Xenograft Model Xenograft procedure angiogenesis annexin A5 aurora-A kinase bevacizumab brain tissue c-myc Genes cancer type cell motility chemotherapy cytotoxicity efficacy testing human STK6 protein hypoxia inducible factor 1 in vitro testing in vivo in vivo Model inhibitor/antagonist irinotecan kinase inhibitor knock-down migration molecular marker mouse model neoplastic cell new therapeutic target novel overexpression radiation response research study response senescence small hairpin RNA small molecule stem stemness taxane temozolomide therapy resistant tumor tumor growth tumor progression vasculogenesis weapons

项目摘要

DESCRIPTION (provided by applicant): Aurora-A (AURKA) is an exciting new drug target for the treatment of glioblastoma (GB). GB is a highly malignant, mostly adult brain tumor for which only marginal improvement in survival time has been achieved. AURKA is a serine-threonine kinase that drives mitotic progression and cytokinesis. It also positively regulates several proproliferative signaling pathways, including c-Myc, cyclin B/CDK1, NF-kB and Wnt signaling and negatively regulates p53. AURKA is oncogenic when overexpressed in cultured cells and its altered expression promotes genomic instability and malignancy. Our preliminary data show that the selective AURKA inhibitor MLN8237 potently inhibits proliferation of GB cells in vitro and extends animal survival in a GB orthotopic xenograft model. We will study the efficacy of MLN8237 against GB patient-derived neurosphere tumor stem-like cells in vitro, and in GB orthotopic xenograft mouse models using neurosphere stem-like cells from multiple patients. Alternate AURKA inhibitors and anti-AURKA RNAi will also be used to verify the efficacy of inhibiting this kinase and to distinguish off-target effects, respectively. These in vitro and animl studies will also investigate the possible synergistic effects of MLN8237 with other GB therapies, e.g., temozolomide, radiation, angiogenesis inhibitors and other chemotherapeutic drugs. We will perform experiments to determine if activated AURKA expression or candidate important interacting proteins, e.g., Bora and TPX2, predict sensitivity to MLN8237, an important step toward understanding which GB patients would likely benefit most from AURKA inhibition. We will determine the mechanisms of AURKA inhibition of tumor growth by examining effects of inhibitors on GB cell apoptosis, differentiation, senescence and genomic stability, as well as the regulation of biochemical pathways mediating these responses. Tumor hypoxia and angiogenesis are important mechanisms of tumor progression in gliomas. AURKA is induced by hypoxia and may itself increase angiogenic factors such as VEGF. We will study the effects of AURKA knockin and knockdown on important angiogenic signaling proteins, e.g., HIF-1�GSK-3�nd VEGF, in cultured cells to investigate possible direct and indirect roles of AURKA in GB angiogenesis. Since AURKA is induced by hypoxia we will test the ability of AURKA inhibitors to potentiate bevacizumab, which may potentially optimize the latter's clinical usefulness. We will also examine measurable biological effects of AURKA inhibition on angiogenesis, tumor invasion and genomic stability using in vitro and animal models.

描述（由申请人提供）：Aurora-A (AURKA) 是一种令人兴奋的治疗胶质母细胞瘤 (GB) 的新药物靶点。 GB 是一种高度恶性的、大多数为成人的脑肿瘤，其生存时间仅略有改善。 AURKA 是一种丝氨酸-苏氨酸激酶，可驱动有丝分裂进程和胞质分裂，还积极调节多种增殖信号通路，包括 c-Myc、细胞周期蛋白 B/CDK1、当在培养细胞中过度表达时，NF-kB 和 Wnt 信号传导并负向调节 p53，其表达改变会促进基因组不稳定和恶性肿瘤。我们的初步数据表明，选择性 AURKA 抑制剂 MLN8237 可有效抑制体外 GB 细胞的增殖并延长动物的增殖。我们将研究 MLN8237 对 GB 患者来源的神经球肿瘤干细胞样的疗效。体外细胞以及使用来自多个患者的神经球干样细胞的 GB 原位异种移植小鼠模型也将分别用于验证抑制该激酶的功效并区分脱靶效应。这些体外和动物研究还将研究 MLN8237 与其他 GB 疗法（例如替莫唑胺、放射、我们将进行实验以确定激活的 AURKA 表达或候选重要相互作用蛋白（例如 Bora 和 TPX2）是否可以预测对 MLN8237 的敏感性，这是了解哪些 GB 患者可能从 AURKA 抑制中受益的重要一步。我们将通过检查抑制剂对GB细胞凋亡、分化、衰老和基因组稳定性的影响以及生化途径的调节来确定AURKA抑制肿瘤生长的机制肿瘤缺氧和血管生成是神经胶质瘤肿瘤进展的重要机制，AURKA 本身可能会增加血管生成因子，例如 VEGF。 HIF-1�GSK-3�nd VEGF，在培养细胞中研究 AURKA 在 GB 血管生成中可能的直接和间接作用。我们将测试 AURKA 抑制剂增强贝伐珠单抗的能力，这可能会优化后者的临床用途。我们还将使用体外和动物模型检查 AURKA 抑制对血管生成、肿瘤侵袭和基因组稳定性的可测量的生物效应。