新型小分子64B靶向抑制眼脉络膜黑色素瘤肝转移的分子机制

项目名称： 新型小分子64B靶向抑制眼脉络膜黑色素瘤肝转移的分子机制

项目编号： No.81502544

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 游硕

作者单位： 中南大学

项目金额： 18万元

中文摘要： 眼脉络膜黑色素瘤是最常见的成人眼部原发肿瘤，肝脏是该肿瘤最先和最常见的转移部位。针对眼脉络膜黑色素瘤肝转移的分子机制进行靶向治疗是提高患者生存率，改善患者生存质量的关键，我们前期数据显示HIF-1在该肿瘤从眼部原发灶转移至肝脏的不同阶段中起重要作用，靶向HIF-1对于阻断眼脉络膜细胞从休眠微转移灶到无血管转移灶再到血管化肝脏大转移灶中具有重要意义。我们新近发现了一个新的小分子化合物64B，具有全新的HIF抑制功能，显示出极强的体内外抗血管生成能力。在此基础上，本研究拟以HIF-1介导的眼脉络膜黑色素瘤肝脏转移的分子机制为切入点，利用新型小分子64B针对HIF-1信号通路靶向抑制眼脉络膜黑色素的肝脏转移，探讨64B在阻断眼脉络膜黑色素瘤肝脏转移中的作用机制，为临床上靶向HIF-1治疗眼脉络膜黑色素瘤及其肝脏转移提供新的思路和实验数据支持。

中文关键词： C25_其它肿瘤；眼脉络膜黑色素瘤；肝转移；新型小分子64B

英文摘要： Uveal melanoma is the most common primary eye tumor in adults and liver is the first and most common site for its metastasis. Therefore, by targeting the molecular mechanisms of how uveal melanoma metastasize to the liver is the key to improve both patient survival rate and life quality. Our preliminary data indicates that HIF-1 plays a vital role in various stages of the uveal melanoma liver metastases process. HIF-1 may be an important therapeutic target for uveal melanoma liver metastasis as it is involved in the process of avascular metastases development from dormant micro metastasis and also further expansion into vascularized macro metastases. Recently, we discovered a new small molecule 64B which demonstrated novel HIF inhibition capacity. The compound also demonstrated potent in vivo anti-angiogenesis effects. Based on our data, this proposal aims to discuss the important role of HIF-1 mediated uveal melanoma liver metastases process and explore the possibility of using our novel small molecule 64B to block such metastases process. We will further explore the possible mechanisms of HIF-1 inhibition by 64B during the different stages of uveal melanoma liver metastases blockage. In summary, the current study will provide new strategies and experimental data support for targeting HIF-1 as a novel targeted therapy for treatment of uveal melanoma and its liver metastases.

英文关键词： other tumors;uveal melanoma;liver metastasis;new small molecule 64B