Antiangiogenic drugs: Chemosensitizers for combination cancer therapy

Angiogenesis is a key step in tumor progression and recurrence, and is known as a hallmark of solid tumors. The architecture of the tumor vasculature is deregulated, vessels are immature, and their functionality is defective, causing increase of interstitial pressure, hypoxia, and acidity in the tumor microenvironment, and favoring an enhanced tumor dissemination and metastasis. The defective tumor vasculature as well as the modifications of tumor microenvironment are a barrier for the effective delivery and accumulation of either the anticancer drugs, including antiangiogenic drugs, or immune-competent T cells in tumor area, thus promoting tumor resistance to therapy. Among the various approaches for targeting tumor angiogenesis, vascular normalization and vessel maturation are considered the most promising approaches, which favor both an effective delivery of anticancer drugs and accumulation of immune-competent T cells into the tumor area. Antiangiogenic therapy can downregulate continuous angiogenic signaling and result in vascular normalization, such as pruning, vascular maturation, and increased perfusion. Thus, antiangiogenic drugs are now considered promising chemosensitizers of anticancer strategies such as chemotherapy, target therapies, and immune checkpoint inhibitors in several advanced tumors. This review summarizes the current understanding and clinical development of combination therapy with antiangiogenic drugs and anticancer chemo-, targeted, and immune therapies.