Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives.
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.
Shen
Ying-Chun
YC
National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
Hsu
Chiun
C
Cheng
Ann-Lii
AL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D018579:Patient Selection; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib