(IND 102,133) Inhibition of Aurora Kinase A as Treatment For Melanoma

项目摘要/摘要 黑色素瘤在男性中的增长速度比其他任何癌症都要高，是女性增长第二快的癌症。 在美国，如果及早诊断，这种疾病是可以治愈的。然而，播散性疾病的5年存活率为 6%。化疗几乎没有好处，而免疫治疗只对少数黑色素瘤患者有效。 目前迫切需要有效的治疗方法。针对特定信号通路的治疗的成功 在其他癌症中，已经加强了对黑色素瘤关键途径的搜索，已经有了潜在的靶点 已确认身份。极光激酶A(AURKA)对于正常的有丝分裂和细胞周期通过G2-2的进程是必不可少的。 M转换。AURKA在许多恶性肿瘤中过度表达或激活。肿瘤的致癌特性 AURKA过表达包括非整倍体、胞质分裂失败、基因组完整性受损和抑制 通过P53发出信号。对AURKA的RNAi导致人类有丝分裂延迟、有丝分裂纺锤体缺陷和细胞凋亡 癌细胞。MLN8237是千禧公司开发的一种治疗AURKA的选择性小分子抑制剂 晚期恶性肿瘤。我们最近看到AURKA在转移性肿瘤中的高水平表达 黑色素瘤。我们还观察到一种效力较低的AURKA抑制剂在新鲜的 大量黑色素瘤患者的人-裸鼠异种移植。拟议中的MLN8237试验 黑色素瘤的独特之处在于它使用手术前患者来确定体内肿瘤靶向抑制的标志物。 然后利用这一知识来评估靶抑制与临床结果的关系 晚期黑色素瘤。识别响应的预测生物标记物可以允许选择和监测 在随后的临床试验中使用这种药物的患者。第二阶段试验将确定MLN8237的临床活性 患有晚期黑色素瘤。黑色素瘤的分子特征可能使我们能够识别出 基因分型。这项试验应该提供关于分子靶标(AURKA)存在的有价值的信息， 靶标的抑制，以及对癌细胞和肿瘤微环境内下游事件的影响。 更好地理解有效治疗的基础，甚至是无效治疗的机制将是 对了解如何进行该药物的开发至关重要，并可能影响对 其他药物。

Project Summary/Abstract Melanoma is increasing among men more than any other cancer and is the 2nd fastest rising cancer in women in the U.S. The disease is curable if diagnosed early. However, disseminated disease has a 5 year survival of <6%. Chemotherapy has little benefit, while immunotherapy has an impact on only a few melanoma patients. Effective treatments are desperately needed. The success of therapy targeted at specific signaling pathways in other cancers, has intensified the search for critical pathways in melanoma , with potential targets already identified. Aurora kinase A (AURKA) is essential for normal mitosis and cell cycle progression through the G2- M transition. AURKA is overexpressed or activated in a number of malignancies. Oncogenic properties of AURKA overexpression include aneuploidy, cytokinesis failure, impaired genomic integrity, and inhibition of signaling through p53. RNAi to AURKA leads to mitotic delay, mitotic spindle defects, and apoptosis in human cancer cells. MLN8237 is a selective small molecule inhibitor of AURKA developed by Millenium for treatment of advanced malignancies. We have recently seen high levels of expression of AURKA in metastatic melanoma. We have also observed consistent anti-tumor activity with a less potent AURKA inhibitor in fresh human-nude mouse xenografts dervied from numerous melanoma patients. The proposed trial of MLN8237 in melanoma is unique in its use of the pre-surgical patient to define markers of target inhibition in vivo at tumor sites, and then to use this knowledge to assess the relationship of target inhibition with clinical outcome in advanced melanoma. Identifying predictive biomarkers of response may allow the selection and monitoring of patients in subsequent clinical trials with this agent. The phase II trial will define the clinical activity of MLN8237 in advanced melanoma. Molecular characterization of the melanomas may allow us to identify a responsive genotype. This trial should provide valuable information about the presence of a molecular target (AURKA), inhibition of the target, and effects on downstream events within the cancer cell and tumor microenvironment. A better understanding of the basis for effective or even the mechanism underlying ineffective therapy will be critical to understanding how to proceed in the development of this drug and may influence the evaluation of other drugs.