Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related mortality worldwide. Despite decades of efforts by many investigators, systemic chemotherapy or hormonal therapy has notoriously failed to show an improvement in survival. With a median survival of 8 months, and 1- and 3-year survival rates of 20% and 5%, respectively, the effective treatment of HCC remains far from satisfactory. Better understanding of the pathogenesis of this disease, identification of molecular targets for therapeutic intervention and availability of promising molecularly targeted therapies may change this dismal picture. In this review we will focus on what is currently known about the molecular pathogenesis of HCC, and explore the currently available and future molecular based therapies targeting these pathways. Future research in this area will maximize clinical benefit while minimizing the toxicity and cost through utilization of novel targeted agents.
Highlights
The fifth most common cancer worldwide and the third most common cause of cancer-related deaths globally, Hepatocellular carcinoma (HCC) poses a great challenge [1,2]
A randomized phase III study comparing sunitinib at 37.5 mg continuous daily dosing versus sorafenib at 400 mg twice daily in advanced HCC was terminated on April 22th, 2010, based on a higher incidence of serious adverse events in the sunitinib arm compared to the sorafenib arm, and the fact that sunitinib did not meet the criteria to demonstrate that it was neither superior or non-inferior to sorafenib in the survival of patients with advanced hepatocellular cancer
Since the emergence of sorafenib as the new standard for the systemic treatment of advanced HCC, extensive research efforts have focused on several key molecular pathways implicated in the pathogenesis of HCC
Summary
The fifth most common cancer worldwide and the third most common cause of cancer-related deaths globally, HCC poses a great challenge [1,2]. Due to multiple etiologies leading to the development of this disease, HCC patient populations are very diverse. It can occur in various underlying settings such as hepatitis B and C, nonalcoholic steatohepatitis, hemochromatosis, autoimmune hepatitis, alcohol-related liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis. Improved understanding of the mechanism of hepatocarcinogenesis, coupled with the discovery of a multitude of molecular pathways leading to the development of HCC, has created a great opportunity to identify new targets and effective therapies (Figure 1). The initial demonstration of improved survival benefit by sorafenib in advanced HCC has opened a new era of molecularly targeted therapies, resulting in the discovery of a diverse spectrum of novel agents, many of which are currently under active clinical investigation and development. In this article we will review the pathways identified in the pathogenesis of HCC along with currently available and in development therapies targeting these pathways
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