Aurora-A is a novel therapeutic target in glioblastoma

Aurora-A 是胶质母细胞瘤的新治疗靶点

• 批准号: 8818801
• 负责人: NORMAN LEHMAN
• 金额: $ 36.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8818801
• 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; 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; public health relevance; research study; response; senescence; small hairpin RNA; small molecule; stem; stemness; taxane; temozolomide; therapy resistant; tumor; tumor growth; tumor progression; vasculogenesis; weapons

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）的新药靶点。GB是一种高度恶性的，主要是成人脑肿瘤，其生存时间仅略有改善。AURKA是驱动有丝分裂进程和胞质分裂的丝氨酸-苏氨酸激酶。它还积极调节几种促增殖信号传导途径，包括c-Myc、细胞周期蛋白B/CDK 1、NF-κ B和Wnt信号传导，并消极调节p53。AURKA在培养细胞中过表达时是致癌的，其表达改变促进基因组不稳定和恶性。 我们的初步数据表明，选择性AURKA抑制剂MLN 8237在体外有效抑制GB细胞增殖，并延长GB原位异种移植模型中的动物存活期。我们将在体外研究MLN 8237对GB患者源性神经球肿瘤干细胞样细胞的疗效，并在GB原位异种移植小鼠模型中使用来自多名患者的神经球干细胞样细胞。替代AURKA抑制剂和抗AURKA RNAi也将分别用于验证抑制该激酶的功效和区分脱靶效应。这些体外和动物研究还将研究MLN 8237与其他GB治疗（例如，替莫唑胺、放射、血管生成抑制剂和其它化疗药物。我们将进行实验，以确定是否激活AURKA表达或候选的重要相互作用蛋白，例如，Bora和TPX 2预测对MLN 8237的敏感性，这是了解哪些GB患者可能从AURKA抑制中获益最多的重要一步。我们将通过研究抑制剂对GB细胞凋亡、分化、衰老和基因组稳定性的影响，以及介导这些反应的生化途径的调节，来确定AURKA抑制肿瘤生长的机制。 肿瘤缺氧和血管生成是胶质瘤进展的重要机制。AURKA是由缺氧诱导的，本身可能会增加血管生成因子，如VEGF。我们将研究AURKA敲入和敲低对重要的血管生成信号蛋白的影响，例如，HIF-1、GSK-3和VEGF在体外培养的细胞中的表达，以研究AURKA在GB血管生成中可能的直接和间接作用。由于AURKA是由缺氧诱导的，我们将测试AURKA抑制剂增强贝伐单抗的能力，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研究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学效应。