Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives

Abstract

Novel cancer therapies targeting tumor angiogenesis have revolutionized treatment options in a variety of tumors. Specifically, VEGF signaling pathway (VSP) inhibitors have been introduced into clinical practice at a rapid pace over the last decade. It is becoming increasingly clear that VSP inhibitors can cause cardiovascular toxicities including hypertension, thrombosis, and heart failure. This review highlights these toxicities and proposes several strategies in their prevention and treatment. However, we recognize the dearth of data in this area and advocate a multi-disciplinary approach involving cardiologists and oncologists, as well as clinical and translational studies, in understanding and treating VSP-inhibitor associated toxicities.

Figure 1. Mechanisms of VEGF signaling pathway inhibitors

Multiple strategies have been employed to pharmacologically target the VEGF signaling pathway. One anti-VEGF monoclonal antibody has been developed (bevacizumab). Multiple tyrosine kinase inhibitors (TKIs) target the intracellular kinase domain on the VEGF receptors, as well as on other important tyrosine kinases. Five currently approved VSP inhibitors fall into this category (sunitinib, sorafenib, axitinib, pazopanib, and vandetanib). Numerous other TKIs are in various stages of development or trials. Other approaches to VSP inhibition that are currently in development or clinical trials include a soluble VEGF receptor, or VEGF-Trap, and a monoclonal antibody generated against VEGFR2.

Figure 2. Signaling pathways downstream of VEGFR2 in endothelial cells

VEGFR2 is the primary VEGFR that mediates angiogenic signaling. Numerous pathways are activated in response to VEGF binding to VEGFR2. Notably, endothelial nitric oxide synthase (eNOS) is activated by multiple pathways including PKC and AKT/PKB, leading to an increase in vascular permeability and a decrease in vascular resistance. Signaling through Ras and PI3K-AKT promotes cell survival and proliferation. FAK and p38/MAPK signaling promote cellular mobility and migration. These pathways promote increased endothelial cell survival, proliferation, and migration, culminating in increased angiogenic potential. AKT/PKB, protein kinase B; cPLA2, cytoplasmic phospholipase 2; DAG, diacylglycerol; ERK, extracellular signal-regulated kianse; FAK, focal adhesion kinase; MEK, mitogen-activated protein kinase kinase; NO, nitric oxide; PGI2, prostaglandin I₂; PI3K, phosphotidylinositol-3 kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ; p38/MAPK, mitogen-activated protein kinase.