National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
J Gastroenterol. 2010 Aug;45(8):794-807. doi: 10.1007/s00535-010-0270-0. Epub 2010 Jun 22.
Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)-mediated angiogenesis, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). This advance has shifted the paradigm of systemic treatment for HCC toward molecular targeted therapy (MTT). However, the disease-stabilizing effect of VEGF signaling-targeted MTT normally lasts only for a few months, suggesting a rapid emergence of resistance in the majority of patients. To overcome the resistance to VEGF signaling-targeted MTT, strategies incorporating inhibition of either compensatory pro-angiogenic pathways or recruitment of bone marrow-derived circulating endothelial progenitors, as well as suppression of other oncogenic pathways, are currently being investigated. The combination of multiple molecular targeted agents or the use of multi-target agents may enhance the efficacy at the expense of increased toxicities. To facilitate the development of MTT for HCC, current methodologies for pharmacodynamic assessment, patient selection and target identification need to be improved. Patient selection according to the individual molecular signature of the tumor and correlative biomarker studies are encouraged while planning a clinical trial of novel MTT.
索拉非尼是一种多激酶抑制剂，可靶向血管内皮生长因子（VEGF）介导的血管生成，是首个被发现可延长晚期肝细胞癌（HCC）患者生存时间的药物。这一进展将 HCC 的系统治疗模式转向了分子靶向治疗（MTT）。然而，VEGF 信号靶向 MTT 的疾病稳定作用通常仅持续数月，提示大多数患者会迅速产生耐药性。为了克服对 VEGF 信号靶向 MTT 的耐药性，目前正在研究联合抑制代偿性促血管生成途径或招募骨髓源性循环内皮祖细胞，以及抑制其他致癌途径的策略。联合使用多种分子靶向药物或使用多靶点药物可能会提高疗效，但同时也会增加毒性。为了促进 HCC 的 MTT 发展，需要改进目前用于药效评估、患者选择和靶点识别的方法。在计划新型 MTT 的临床试验时，鼓励根据肿瘤的个体分子特征和相关生物标志物研究进行患者选择。
