COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E₂ (PGE₂) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE₂ production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE₂ pathway inmediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.