State-of-the-Art in Antiangiogenic Agents in Cancer Therapy

Anti-angiogenesis is the therapeutic strategy designed to disrupt the vascular supply and starve tumors of nutrients and oxygen. This is achieved mainly by blocking the vascular endothelial growth factor (VEGF) actions, as the VEGF signaling pathway is considered the main angiogenesis promoter and is active in the tumor microenvironment (TME) under hypoxic conditions. A total of 16 anti-angiogenic agents, including anti-VEGF antibodies, anti-VEGF receptor (VEGFR) antibodies, as well as VEGFR tyrosine kinase inhibitors (TKIs), have been approved for certain types of cancer. However, despite the mechanistic rationale that strongly supports the benefit of antiangiogenics to stop cancer progression, both in monotherapy or in combination with chemotherapy or targeted therapies, the antiangiogenics demonstrated limited clinical benefits for most patients with cancer. A recent hypothesis is that the "normalization" of the entire TME through a combination of antiangiogenics with immune therapies and/or inhibitors of tumor-associated stromal cells could present a potential synergistic anti-tumor effect. The TME imprinting converges in epigenetic modifications in endothelial cells that switch to tumor pro-angiogenic endothelial cells and continue to support the aggressiveness of tumor cells, including resistance to antiangiogenic therapies. The present review summarizes the current status of antiangiogenic strategies, the molecular mechanisms underlying their failure, and we discuss some alternative mechanisms targeting angiogenesis.