Aurora-A is a novel therapeutic target in glioblastoma

描述(由申请人提供)：Aurora-A(AURKA)是治疗胶质母细胞瘤(GB)的令人兴奋的新药靶点。胆囊癌是一种高度恶性的脑肿瘤，大多数是成人脑瘤，生存时间只有轻微的改善。AURKA是一种丝氨酸-苏氨酸激酶，可以驱动有丝分裂进程和胞质分裂。它还正向调节几个促增殖信号通路，包括c-Myc、细胞周期蛋白B/CDK1、核因子-kB和Wnt信号通路，负向调节P53。当AURKA在培养细胞中过表达时，它是致癌的，其表达的改变促进了基因组的不稳定和恶性。我们的初步数据显示，选择性AURKA抑制剂MLN8237在体外有效地抑制了GB细胞的增殖，并延长了GB原位异种移植模型的动物存活时间。我们将研究MLN8237在体外对GB患者来源的神经球肿瘤干细胞的疗效，以及在GB同种异种移植小鼠模型中使用多名患者的神经球样干细胞。替代的AURKA抑制剂和抗AURKA RNAi也将分别用于验证抑制该激酶的有效性和区分靶外效应。这些体外和动画研究还将探讨MLN8237与其他GB疗法，如替莫唑胺、放射、血管生成抑制剂和其他化疗药物的可能协同作用。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，如BORA和TPX2，是否预测对MLN8237的敏感性，这是了解哪些GB患者可能从AURKA抑制中受益最大的重要一步。我们将通过检测抑制剂对GB细胞的凋亡、分化、衰老和基因组稳定性的影响，以及调节这些反应的生化途径，来确定AURKA抑制肿瘤生长的机制。肿瘤缺氧和血管生成是脑胶质瘤发生发展的重要机制。AURKA是由低氧诱导的，本身可能会增加血管生成因子，如血管内皮生长因子。我们将研究AURKA基因敲除和敲除对培养细胞中重要的血管生成信号蛋白如HIF-1、�、GSK-3、�和血管内皮生长因子的影响，以探讨AURKA基因在银屑病血管生成中可能的直接和间接作用。由于AURKA是由低氧诱导的，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应用。我们还将使用体外和动物模型检测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。

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.