Molecular Targeted Therapy for Hepatocellular Carcinoma: Bench to Bedside

Abstract

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.

Heparin Inhibits Hepatocyte Growth Factor Induced Motility and Invasion of Hepatocellular Carcinoma Cells through Early Growth Response Protein 1

“…The stimulatory effects of HGF on the motility and invasion of HCC cells are well documented [1], [5], [31], [32], and activation of cell motility and invasion are also rate-limiting steps of tumor metastasis [33]. Concordantly, the activation of HGF/c-Met signaling positively correlates with tumor metastasis in HCC [1].…”

Association of Polymorphism in Pri-microRNAs-371-372-373 with the Occurrence of Hepatocellular Carcinoma in Hepatitis B Virus Infected Patients

“…The diverse action mechanisms of the miRNAs-371-373 cluster on various cancer occurrence have been suggested; for example, collaboration with oncogenic Ras and neutralization of p53-mediated cyclin-dependent kinase inhibition [34], promotion of tumor invasion and metastasis by suppression of CD 44 [37], or modulation of Wnt/β-catenin-signaling pathways [38]. These are also known molecular signals in HCC [39], [40], therefore these signals can be possible mechanisms for the effects of pri-miRNAs-371-373 polymorphisms on HCC occurrence.…”

Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis: Implications for the treatment of human liver cancer

“…In HCC, deregulation of the PI3K/AKT/mTOR pathway is the result of multiple molecular mechanisms, including activated mutations of PI3K p110 (PIK3CA) catalytic subunit, loss of expression of its negative regulator, phosphatase and tensin homolog (Pten) or aberrant activation of receptor tyrosine kinases 11 , 12 . The importance of the PI3K/AKT/mTOR pathway in hepatocarcinogenesis is underscored by the finding that mTOR inhibition suppresses HCC growth in vitro and xenograft models 6 .…”