抗转移新药的靶分子发现、验证、及其信号通路分析

约90%的癌症死亡是由癌细胞的远处转移所造成。肿瘤转移是绝大多数抗癌治疗失败的主要原因。但临床上鲜有抗肿瘤转移药物。“肿瘤转移机制与抗肿瘤转移新药研发” 是科协颁布的我国重大科学问题和工程技术难题之一。而如何发掘一批抗转移的药物靶点就成了业界的当务之急。我们先前建立的高转移和低转移细胞株可用于筛选抗转移药物。为此我们提出科学假说：通过运用基于细胞关键骨架蛋白表达水平的高通量药筛系统，可以发现一批抗肿瘤转移的先导化合物，进而验证一批抗肿瘤转移的药物靶分子。前期预实验显示：我们自创的药物筛选体系稳定高效，在14547个化合物/药物中筛出42个高效低毒的抗转移先导化合物或老药新用，并预测了一批药物靶点。本项目拟通过先导化合物标记、高效液相色谱、蛋白质普、基因敲除与基因突变、体内外功能实验等一系列技术，发现并验证一批抗肿瘤转移的药物靶点、评价靶点的临床意义，为将来的抗转移新药研发奠定坚实的基础。

About 90% of cancer deaths are caused by distant metastasis. Metastasis is the main reason of treatment failure in many malignancies. However, there is very few clinically available anti-metastasis drugs. “The mechanisms underlying cancer metastasis and the development of anti-metastasis drugs” has been selected by the China Association for Science and Technology to be one of the most important scientific question or engineering technological issue in China in 2018. It is therefore critical to identify a batch of drugable targets for anti-metastasis drug development. Our previously established high- and low-metastasis cell lines are useful for developing a screening system for identifying anti-metastasis compounds/drugs. We herein propose a hypothesis: By using cell-based screening system with the readouts of the expression levels of critical cellular skeleton molecules, we would be able to identify some anti-metastasis compounds followed by characterization, confirmation and validation of their drug targets. Our preliminary data showed that the home-made screening system was highly efficient and stable, which was able to identify 42 anti-metastasis lead compounds from 14547 compounds/drugs with high efficacy and low toxicity. We have further predict their drug targets by using computerized analyses. In the proposed study, we will conduct comprehensive studies to identify and further confirm the anti-metastasis drugable targets by compound labelling, high performance liquid chromatography, proteomic analysis, gene engineering for mutation analysis, in vitro cellular models and in vivo animal models. Taken together, the accomplishment of the proposed study will identify and characterize a batch of anti-metastasis drugable targets followed by evaluation of the clinical values of these drug targets, which will pave a solid foundation for the development of anti-metastasis drugs.