Tie Jeanne, Desai Jayesh
Royal Melbourne Hospital, Western Hospital, and Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
Crit Rev Oncog. 2012;17(1):51-67. doi: 10.1615/critrevoncog.v17.i1.50.
Angiogenesis is critical to the growth of human tumors and the development of metastasis. Amongst the many proangiogenic mechanisms identified, the vascular endothelial growth factor (VEGF) signaling pathway has been implicated as the key regulator of tumor neovascularisation. Various therapeutic agents targeting the VEGF pathway have been successfully developed, with many now approved and in routine clinical use. In general, VEGF-mediated angiogenesis can be inhibited by 2 approaches: antibodies directed against VEGF ligands or VEGF receptors (VEGFRs) and tyrosine kinase inhibitors targeting the VEGFRs. Thus far, clinical benefits achieved with VEGF-targeted agents are limited by their modest efficacy and the development of resistance. With no shortage of drugs in development, the lack of well-validated biomarkers to predict for response or resistance to VEGF-directed therapies is now becoming a key factor limiting the further rational development of this class of anticancer agent. This review discusses the biology of VEGF signaling, the clinical efficacy of VEGF-targeting therapies, potential mechanisms of resistance, and emerging predictive biomarkers.
血管生成对于人类肿瘤的生长和转移的发展至关重要。在已确定的众多促血管生成机制中，血管内皮生长因子（VEGF）信号通路被认为是肿瘤新血管形成的关键调节因子。各种针对VEGF通路的治疗药物已成功研发出来，许多现已获批并在临床常规使用。一般来说，VEGF介导的血管生成可以通过两种方法来抑制：针对VEGF配体或VEGF受体（VEGFRs）的抗体以及靶向VEGFRs的酪氨酸激酶抑制剂。到目前为止，VEGF靶向药物所带来的临床益处受到其疗效一般以及耐药性产生的限制。尽管有大量处于研发阶段的药物，但缺乏经过充分验证的生物标志物来预测对VEGF导向治疗的反应或耐药性，这正成为限制这类抗癌药物进一步合理研发的关键因素。本综述讨论了VEGF信号传导的生物学特性、VEGF靶向治疗的临床疗效、潜在的耐药机制以及新出现的预测性生物标志物。
