Molecular pathogenesis and targeted therapy of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) constitutes the 5th most frequent cancer worldwide, and due to a lack of treatment options, HCC represents the 3rd most lethal cancer worldwide. The incidence of HCC is continuously rising in Europe and Northern America, which can be explained by spreading of hepatitis C virus infections. Systemic chemotherapy is not an option for most patients with HCC. The most promising strategy for systemic treatment of HCC is targeted therapy. Successful targeted therapy has to inhibit pathways which are necessary for tumor growth, even in the late stages of carcinogenesis. The p16/Rb, p53, and IGF2R checkpoints as well as oncogenic alterations of telomerase, c-myc, Wnt/beta-catenin, PI3K/Akt, hedgehog, and c-met/HGF are most frequently involved in human hepatocarcinogenesis. However, currently, the most attractive target for molecular therapy of HCC appears to be the vascular endothelial growth factor (VEGF). Phase I/II studies showed high progression-free survival rates with antibodies or small molecules targeting the VEGF receptor pathway. Recently, a randomized placebo-controlled phase III study showed that the multikinase inhibitor sorafenib, which inhibits VEGF and Raf, significantly improves survival of patients with advanced HCC and Child A cirrhosis. As a consequence of this study, sorafenib is now the first available drug for effective systemic treatment of patients with advanced HCC.
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Hanover, Germany.
Lars
L
Zender
Stefan
S
Kubicka
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents