Molecular targeted therapy in hepatocellular carcinoma: from biology to clinical practice and future

Hepatocellular carcinoma (HCC) is one of the most lethal cancers globally, particularly in certain regions of the world. Although the major risk factors for HCC have been identified, the specific mechanisms driving hepatocarcinogenesis remain unclear. Sorafenib is the only systemic therapy that has demonstrated an overall survival benefit in patients with advanced HCC and does so primarily through antiangiogenic activity. However, that actual benefit is still relatively small. Extensive research has focused on targeting dysfunctional molecular pathways in HCC. Despite promising preclinical and early-phase studies, other agents have failed to expand upon the efficacy of sorafenib in large-scale randomized trials. As the development of treatment options in the post-sorafenib setting is ongoing, more efforts are being focused on (1) evaluation of molecular agents targeting pathogenic, HCC-specific pathways; (2) the combination of targeted and cytotoxic therapies in selected subgroups; and (3) the combination of systemic and locoregional therapies in various settings. This article provides a review of recently completed and ongoing studies of molecular targeted agents in HCC, including a brief description of the biologic rationale behind these agents.