Department of Medicine, University of Erlangen, Erlangen, Germany.
Mol Aspects Med. 2010 Apr;31(2):171-8. doi: 10.1016/j.mam.2010.02.005. Epub 2010 Feb 19.
Although colorectal cancer (CRC) is still one of the leading causes of cancer related death in the western hemisphere, new therapeutic options have increased the overall survival rate of advanced disease from 10 to 18-24months during the past decade. The new therapeutics include biological agents as bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), and cetuximab (Erbitux), an inhibitor of epithelial growth factor receptor (EGFR). Although these biologicals have entered clinical routine due to their encouraging results, their effect has been shown to be limited due to adaptation or previously existing resistance of tumor cells. This has been clearly shown in the case of patients with mutations of K-ras, which lead to resistance against cetuximab. Therefore, several new pathways are currently investigated for therapeutic targeting in CRC. These include WNT-signaling, downstream mediators of EGFR as the mitogen-activated protein kinase (MAPK)- or the phosphatidylinositol 3-kinase (PI3K)-pathway, the hypoxia response system involving hypoxia inducible factor-1 (HIF-1), mechanisms of tumor development following chronic inflammation, and many others. This article will review new molecular targets for the treatment of CRC and discuss possible implications for clinical therapy.
虽然结直肠癌（CRC）仍然是西半球癌症相关死亡的主要原因之一，但在过去十年中，新的治疗选择已将晚期疾病的总生存率从 10%提高到 18-24%。这些新的治疗方法包括生物制剂，如贝伐单抗（阿瓦斯汀），一种针对血管内皮生长因子（VEGF）的单克隆抗体，以及西妥昔单抗（爱必妥），一种表皮生长因子受体（EGFR）抑制剂。尽管这些生物制剂因其令人鼓舞的结果已进入临床常规，但由于肿瘤细胞的适应或先前存在的耐药性，其效果已被证明是有限的。这在 K-ras 突变的患者中得到了明确的证明，这导致了对西妥昔单抗的耐药性。因此，目前正在研究几种新的途径来治疗 CRC。这些途径包括 WNT 信号通路、EGFR 的下游介质，如丝裂原激活蛋白激酶（MAPK）或磷酸肌醇 3-激酶（PI3K）通路、涉及缺氧诱导因子-1（HIF-1）的缺氧反应系统、慢性炎症后肿瘤发展的机制，以及许多其他途径。本文将综述 CRC 治疗的新分子靶点，并讨论其对临床治疗的可能意义。
