There are several novel potential molecules and pathways involved in the pathogenesis of hepatocellular carcinoma (HCC) against which targeted therapies are under development as new drugs for HCC treatment. Heparan sulfate proteoglycans are important mediators of cancer cell signaling. The heparin sulfate-mimetic agent PI-88 and newer derivatives as well as small-molecule inhibitors are being developed for specific targeting of the heparan sulfate-modifying enzymes heparanase and the heparin-degrading endosulfatases sulfatase 1 and sulfatase 2 in cancer. The ubiquitin-proteasome pathway plays a central role in cellular protein degradation, including aberrant degradation of tumor supressor proteins. Proteasome inhibitors, such as bortezomib, appear to target the proteasome in HCC through effects on Akt signaling. Dysregulation of apoptosis is a major phenotype of cancer. The TNF-related apoptosis-inducing ligand and X-linked inhibitor of apoptosis protein are key targets of strategies to induce apoptosis in cancer. The IGF pathway has been implicated in development of HCC. Monoclonal antibodies directed against the IGF-1 receptor are under evaluation for treatment of HCC. The heparan sulfate proteoglycan glypican 3 (GPC3) is one of the most highly expressed proteins in HCC. GPC3 is therefore a natural target for therapy of HCC. A humanized monoclonal antibody against GPC3 is in clinical trials for HCC treatment. Inhibitors of the oncogenic Hedgehog, Myc and Wnt/b-catenin signaling pathways are also in preclinical development and of potential use for treatment of HCC.
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