Targeting Receptor Tyrosine Kinase Pathways in Hepatocellular Carcinoma

Hung      Huynh; Richard      Wei Jie Ong; Peter      Yi Qing Li; Swee      Shean Lee; Shu      Yang; Lih      Wen Chong; Danh      Anh Tuan Luu; Chun      Tzen Jong; Irene      Wei Ling Lam

doi:10.2174/187152011796011055

Abstract

Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide with 660,000 deaths annually. Studies of the molecular pathophysiology of HCC have shown that growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in HCC. Activation of these receptors and their downstream signaling pathways can lead to angiogenesis, cell proliferation, survival and metastasis of HCC. Hence, agents that specifically block their activation and signaling cascades would be valuable for treatment of HCC. Many small molecular tyrosine kinase inhibitors (TKIs) and antibodies have been tested in various phases of clinical trials. Although sorafenib has been shown to improve overall survival of patients with advanced HCC, the improvement is marginal and many patients eventually turn out to be refractory to this therapy. Thus, there is a pressing need to identify new drugs and effective treatments for this fatal disease. This review summarizes the pre-clinical and clinical data on the efficacy of the emerging tyrosine kinase inhibitors as well as the rationale for combination therapies for advanced HCC treatment. Understanding the mechanisms of action of these therapeutic agents and methods of combining these drugs may help to increase their efficacy, reduce toxicity, and improve overall survival and quality of life in patients with HCC.

Keywords: Hepatocellular carcinoma, targeted therapies, tyrosine kinase inhibitors, growth factor receptor, TKIs, DCE-MRI, VEGF, DCE-MRI parameters, VEGFR-2, VEGF inhibition, Dovitinib lactate, PI3K/Akt/mTOR PATHWAY, IMC-A12, therapeutic modality, Jak/Stat pathway