一种新型组蛋白去乙酰化酶抑制剂WW437抗三阴性乳腺癌作用及其机制研究

项目名称： 一种新型组蛋白去乙酰化酶抑制剂WW437抗三阴性乳腺癌作用及其机制研究

项目编号： No.81502604

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： 张涛

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 三阴性乳腺癌（TNBC）是一种恶性程度最高的乳腺癌亚型。近年来研究表明，组蛋白去乙酰化酶（HDAC）可作为治疗TNBC的重要靶点，因此研发新型的HDAC抑制剂（HDACi）对于TNBC的治疗具有重要的科研和临床意义。申请者在前期工作基础上筛选得到一种新型异羟肟酸类HDACi，WW437。体外实验证明WW437不仅能够抑制TNBC细胞的生长，而且能显著抑制TNBC细胞的迁移、侵袭及侵袭性伪足的形成。更重要的是初步的小鼠原位肿瘤模型也验证WW437能够显著抑制TNBC的生长和转移。本项目将在前期实验的基础上利用多种细胞和动物模型深入探究WW437对TNBC的抑制作用。机制研究上，本项目将以WW437抑制TNBC的生长和转移为出发点进行探讨。本项目的顺利完成对阐明HADCi抗TNBC作用机制以及药物研发具有重要意义。

中文关键词： C21_乳腺肿瘤；组蛋白去乙酰化酶抑制剂；三阴性乳腺癌；肿瘤生长；；肿瘤转移

英文摘要： Triple negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer. In recent years, many studies have demonstrated that histone deacetylases (HDACs) is a key therapeutic target of TNBC. Therefore, screening novel HDAC inhibitors (HDACi) with potent efficacy and using them as the treatment for TNBC are of great importance. Here, the applicants identified a novel hydroxamate-based HDACi, WW437. In vitro experiments revealed that WW437 markedly inhibited TNBC cells growth, migration, invasion and the formation of invasive structure. More importantly, our preliminary orthotopic breast cancer animal model revealed that WW437 remarkably renders TNBC tumor regression and impairs tumor metastasis. This project aims to further explore the anti-TNBC effect of WW437 on the basis of our preliminary experiment. Mechanistically, this project will take the anti-TNBC growth and metastasis effect of WW437 as a starting point to deeply elucidate its molecular basis. Our project will provide vital significance for elucidating the mechanism through which HDAC inhibitors suppress TNBC and drug discovery.

英文关键词： breast cancer;histone deacetylases inhibitor;triple negative breast cancer;tumor growth; tumor metastasis