Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

Abstract

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.

Signaling Pathways in Liver Cancer

“…HCC is a hypervascular tumor and many pro-angiogenic factors are over-expressed in HCC cells and in the surrounding microenvironment (Shen et al, 2010). Among them, VEGF receptor signaling is one of the most well studied.…”

“…This result is quite significant since no effective systemic therapy ever existed for patients with advanced hepatocellular carcinoma before the sorafenib trial. There are several other VEGF small molecule inhibitors that are currently being tested in the clinic for HCC treatment including, sunitinib, vatalanib, cediranib, brivanib, and linifanib (Shen et al, 2010;Whittaker et al, 2010). Studies have also been carried out to assess the benefit of the combined therapy using those compounds.…”

Androgen Receptor and Hepatocellular Carcinoma

“…Sorafenib, a molecular-targeted agent that inhibits tumor cell proliferation and angiogenesis by inhibiting Raf serine-threonine kinase (MAPKK kinase, MAPKKK), and VEGF, platelet-derived growth factor beta (PDGF), fms-related tyrosine kinase 3 (FLT3), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (C-Kit) receptor tyrosine kinase, was approved for treatment of advanced HCC in Europe, USA, Japan and other countries [13,14]. A selective transforming growth factor beta-1 receptor inhibits phosphorylation of the beta 1 integrin intracytoplasmic tail, blocking invasion of HCC cells [15].…”

Sorafenib and hepatic arterial infusion chemotherapy for unresectable advanced hepatocellular carcinoma: A comparative study

“…The response rate of advanced HCC to HAIC is approximately 30-40% (9)(10)(11)(12)(13)(14)(15)(16), and HAIC (as well as sorafenib) is recommended for treatment of advanced HCC, particularly in Japan (17,18). However, comparison of the effects of sorafenib with other treatment methods for HCC has not been Sorafenib and hepatic arterial infusion chemotherapy for unresectable advanced hepatocellular carcinoma: A comparative study carried out.…”