胃癌的分子靶向治疗进展

Progression in the molecular classification and targeted therapy of advanced gastric cancer

胃癌被最初诊断时往往处于进展期,其预后极差。多个分子信号通路诸如PI3K/AKT、MAPK通路,或分子突变包括人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)、表皮生长因子受体(epidermal growth factor receptor,EGFR)、血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体(VEGFR)、间质上皮转化因子(mesenchymal-epithelial transition factor,c-MET)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,MTOR)等生长因子及受体家族,参与了胃癌细胞周期调控以及增殖和侵袭迁移、血管生成等过程。针对这些靶点的药物临床试验获得了不同程度的疗效。在这些分子靶向领域中,完成Ⅱ/Ⅲ期临床试验终获成功的只有曲妥珠单抗、雷莫芦单抗及阿帕替尼。一项关于靶向治疗在进展期胃癌的随机试验的系统评价和meta分析表明相比于传统治疗,靶向治疗有着显著的生存获益和可以接受的药物毒性,其主要归功于抗血管生成和抗HER-2药物。

The patients always present with advanced gastric cancer,of which the prognosis is poor.Multiple signal pathways including PI3K/AKT pathway and MAPK pathway,growth factors and receptors including HER-2,EGFR,VEGF/VEGFR,c-MET and MTOR,are involved in the occurrence and development of gastric cancer,all these factors play a key role in cell cycle regulation,proliferation,invasion,migration as well as angiogenesis of gastric malignancy.Clinical trials on targeted drugs related to the molecular classifi cation have achieved varying degrees of effi cacy.In the area of molecular targeted therapy,the approved drugs in clinical trials of phaseⅡandⅢare only trastuzumab,ramucirumab and apatinib.A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer,demonstrated a signifi cant survival benefi t with acceptable tolerability profi le for targeted-based therapies compared to conventional treatments.Dramatically,the survival benefi t could mainly be ascribed to anti-angiogenic and anti-HER2 agents.