项目名称: Aurora-A激酶靶向抑制剂VX-680协同全反式维甲酸治疗急性早幼粒细胞白血病的作用机制研究
项目编号: No.30873084
项目类型: 面上项目
立项/批准年度: 2009
项目学科: 交通运输
项目作者: 刘强
作者单位: 中山大学
项目金额: 38万元
中文摘要: 全反式维甲酸(ATRA)应用于急性早幼粒白血病(APL)是肿瘤诱导分化治疗的里程碑,但耐药性仍是治愈APL的瓶颈,联合治疗成为提高敏感性的有效手段。我们研究发现细胞周期Aurora-A激酶可作为急性髓性白血病(AML)生物学标记物,其小分子抑制剂(VX-680)在AML中具有高效选择性抗癌能力(Blood,2008,111:2854);并观察到VX-680与ATRA联合使用可对APL细胞株产生协同杀伤作用(见研究基础)。在此基础上,本课题拟系统分析此联合用药对ATRA敏感及耐药APL细胞株增殖及分化的影响,同时检测PML/RARa融合蛋白表达水平的变化,阐明其药理作用的分子机制,为药物开发提供新靶点;并通过荷瘤裸鼠模型及临床APL原代细胞进一步验证该联合药效,探索VX-680治疗APL的可行性,为临床应用抑制生长联合诱导分化的治疗方案进而将APL变为真正可治愈的癌症提供新思路。
中文关键词: Aur-A激酶;全反式维甲酸;药理作用;分子机制;靶向治疗
英文摘要: All-trans retinoid acid (ATRA) is used to treat patients suffering from acute promyelocytic leukemia (APL), in which PML-RARa fusion protein preventing myeloblast differentiation. The main reason for treatment failure is chemo-resistance. Enhanced toxicity has been observed in combination targeting in APL cells. Previously, we found that Aurora kinase inhibitory VX-680 increased Bax/Bcl-2 ratio and induced apoptosis in Aurora-A-high acute myeloid leukemia (Blood, 2008, 111:2854). Moreover, VX-680 combined with ATRA showed synergistic effect on inducing apoptotic cell death in APL cells. In this project, we will detect the effect of combination treatment on cellular proliferation and differentiation, as well as the change of PML/RARa expression. Next, we will study the effect of combination treatment in xenograft tumor models and primary APL cells. This study will provide novel insight for anti-APL therapy.
英文关键词: Aurora-A kinase; ATRA;pharmacology;molecular mechanism; target therapy