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.

Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations

“…Antiangiogenic therapy prevents the initiation of neovascularization, thereby slowing tumor growth and inducing tumor regression [Folkman, 2004]. However, evidence suggests that compensatory pathways at the level of the tumor vasculature and microenvironment can promote resistance [Casanovas et al 2005;Li et al 2010;Mizukami et al 2005;Raza et al 2010;Wenger et al 2011;Yu et al 2002]. Multiple resistance mechanisms have been identified and are shown schematically in Figure 1.…”

“…Although recent preclinical and clinical studies have increased our understanding of the mechanisms for resistance to antiangiogenic therapy, they offer limited guidance for effective management of disease progression [Li et al 2010;Raza et al 2010;Wenger et al 2011]. In this review, we discuss key challenges in the management of HCC progression on sorafenib and review novel approaches to treatment of this patient population.…”

Combination of Bevacizumab and Acyclic Retinoid Inhibits the Growth of Hepatocellular Carcinoma Xenografts

“…Several clinical trials have suggested that bevacizumab may be a promising agent for the treatment of advanced HCC (10,11). However, data supporting the ability of this antibody to improve the prognosis of HCC patients are insufficient at present.…”

“…Phase II clinical trials have demonstrated the efficacy of bevacizumab when used as a single agent or in combination with cytotoxic or molecular-targeted agents for the treatment of advanced HCC (10,11). The administration of bevacizumab significantly improved the survival of mice bearing human HCC tumors orthotopically transplanted in the liver (12).…”

Systemic Management of Advanced Hepatocellular Carcinoma Patients: The Role of Multi-Targeted Anti-Angiogenic Inhibitors

“…The vascular remodeling that due to pericytic over-coverage renders the neovasculature less responsive to VEGF for growth dependence effectively circumventing a blocked signaling pathway with greater dependence on other alternate mechanisms [51].…”