转移性大肠癌(mCRC)五年生存率不足20%，缺少有效治疗方式。以转移性大肠癌细胞特异性分子靶点为导向的药物研发有望成为有效治疗的重要突破口。申请者前期通过噬菌体展示技术从转移性大肠癌细胞中筛选并获得能够靶向ANXA2蛋白的大肠癌亲和肽(GV)，验证其具有靶向结合ANXA2并内化进入细胞内实现CRC细胞及荷瘤组织内特异靶向聚集；申请者将GV与促凋亡肽(KLAK)连接构建新型肽聚体(GV-K)，发现GV-K对mCRC细胞株和原代CRC细胞具有特异高效的杀伤作用。本课题拟通过不同层面研究内容设定，确认新型肽聚体GV-K与ANXA2蛋白结合的特定氨基酸位点，明确介导GV-K内化的关键环节；阐明GV-K靶向ANXA2蛋白并随之内化经胞内体-溶酶体途径释放促凋亡肽，激活线粒体CytoC-Apaf-1凋亡途径的作用机制。本项目将为基于转移性大肠癌新靶点研究创新多肽药物与新型诊疗策略奠定理论与实验基础。

The five-year survival rate of metastatic colorectal cancer (mCRC) is less than 20%, and currently there are no effective treatments. The targeting drugs on specific molecular targets of mCRC become a promising therapeutic strategy for the treatment of mCRC. We screened and obtained the tumor affinity peptide GV by the phage display technology from the mCRC cell line SW620 which can target the membrane ANXA2 protein. The tumor affinity peptide GV was verified to be able to target ANXA2 and internalize into the cancer cells. GV also can aggregate in tumor-bearing tissues. The novel peptide polymer GV-K was constructed from GV and the pro-apoptotic peptide (KLAK) by linker. GV-K can specifically and significantly kill the CRC cells whether cell lines or the primary culture cells by internalizing into the CRC cells. The purpose of this project is to identify the specific amino acid sites of the interaction between GV-K and ANXA2 protein, to confirm the key regulatory factors of GV-K internalization, to clarify the mechanism which GV-K targets ANXA2 protein, internalizes and releases the pro-apoptotic peptides through protease hydrolysis in lysosome which activating the mitochondrial Cyto-Apaf-1 apoptotic pathway. We believe that achieving these goals provides the theoretical and experimental basis for screening of new drug therapeutic targets and novel peptide drugs for mCRC.