Molecular targeted therapy for hepatocellular carcinoma: bench to bedside

According to the International Agency for Research on Cancer, approximately 670,000 new cases of hepatocellular carcinoma (HCC) developed in 2005, making it the fifth most common cancer and third most common cause of cancer-related death worldwide. HCC is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as EGFR, Ras/Raf/MEK, PI3K/mTOR, HGF/MET, Wnt, Hedgehog and apoptotic signaling pathway. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. It has been proposed that signaling pathway disruption in cancer can be grouped in six function capabilities, some of which need to be altered for cancer development: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis and tumor invasion and metastases. The aim is to integrate these concepts into the molecular pathogenesis of HCC. It has also been proposed that there are common disturbances universal to all liver cancers on top of the more specific mechanisms. Based on this basic research, a molecular targeted agent has recently been developed. There have been no effective chemotherapeutic agents for advanced HCC. Sorafenib, an oral multikinase inhibitor, has set a milestone in the management of HCC in that it is the first agent to significantly improve the overall survival in patients with advanced HCC in a double-blind, placebo-controlled, phase III study. Clinical trials testing new agents for first- and second-line agents, as well as in combination with existing treatment options such as transarterial chemoembolization or arterial infusion chemotherapy, are ongoing. The results of these trials are therefore eagerly awaited.