Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma?

Abstract

Antiangiogenic therapy has shown promise in the treatment of patients with hepatocellular carcinoma (HCC). Bevacizumab, sorafenib, and sunitinib showed efficacy in patients with HCC; and sorafenib is approved by the FDA for treatment of this cancer. In practice, the clinical benefit of these agents has been heterogeneous; and in patients who do respond, the benefit is modest and/or short-lived. Recent advances in the molecular understanding of tumor angiogenesis along with the rapid development of targeted drug discovery have made it possible to explore novel combination therapy for HCC. We review the clinical trial results, discuss possible molecular mechanisms of resistance, and suggest novel combinations with antiangiogenic therapy.

Fig. 1

Diagram depicting the tumor microenvironment and mechanism of known HIF inhibitors. HIF-α is overexpressed in cancer cells and stromal cells, promoting tumor angiogenesis by inducing the production of VEGF and other proangiogenic factors. HIF inhibitors work by disrupting HIF-α protein synthesis, stability, or transcriptional activity. PHD prolyl hydroxylase, HIF-α hypoxia-inducible factor-α, HIF-β hypoxia-inducible factor-β, pVHL von Hippel-Lindau protein, HDAC histone deacetylase, HSP90 heat shock protein 90, mTOR mammalian target of rapamycin, p300 transcriptional coactivator p300, EGFR epidermal growth factor receptor, VEGF vascular endothelial growth factor, PDGF platelet-derived growth factor