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

描述(由申请人提供)： 黑色素瘤在男性中的增长速度比其他任何癌症都要高，是美国女性增长第二快的癌症。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。需要有效的治疗方法。针对其他癌症特定信号通路的治疗的成功，加强了对黑色素瘤关键通路的搜索，潜在的靶点已经确定。极光激酶A(AURKA)对于正常的有丝分裂和细胞周期通过G2-M过渡是必不可少的。AURKA在许多恶性肿瘤中过度表达或激活。AURKA过表达的致癌特征包括非整倍体、胞质分裂失败、基因组完整性受损和通过p53抑制信号。对AURKA的RNAi导致人类癌细胞有丝分裂延迟、有丝分裂纺锤体缺陷和细胞凋亡。MLN8237是千禧公司开发的一种选择性AURKA小分子抑制剂，用于治疗晚期恶性肿瘤。申请人最近在转移性黑色素瘤中看到了AURKA的高水平表达。他们还观察到，在来自许多黑色素瘤患者的新鲜人-裸鼠异种移植中，一种效力较低的AURKA抑制剂具有一致的抗肿瘤活性。MLN8237治疗黑色素瘤的拟议试验的独特之处在于，它使用手术前患者在肿瘤部位定义体内靶点抑制的标记物，然后利用这一知识来评估晚期黑色素瘤的靶点抑制与临床结果的关系。识别反应的预测生物标志物可能允许在随后的临床试验中选择和监测患者使用该试剂。第二阶段试验将确定MLN8237在晚期黑色素瘤中的临床活性。黑色素瘤的分子特征可以使申请者识别出有反应的基因。这项试验应该提供关于分子靶点(AURKA)的存在、靶点的抑制以及对癌细胞和肿瘤微环境中下游事件的影响的有价值的信息。更好地了解有效治疗的基础，甚至无效治疗的机制，将对了解如何继续开发这种药物至关重要，并可能影响对其他药物的评估。

DESCRIPTION (provided by applicant): 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 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. The applicant has recently seen high levels of expression of AURKA in metastatic melanoma. They have also observed consistent anti-tumor activity with a less potent AURKA inhibitor in fresh human-nude mouse xenografts derived 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 the applicant 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.