Emerging enzymatic targets controlling angiogenesis in cancer: preclinical evidence and potential clinical applications

Angiogenesis has always been considered as a fundamental therapeutic target for inhibiting tumor growth and metastasis. To date, anti-angiogenic treatments that have been approved are principally based on either administration of monoclonal antibodies targeting the vascular endothelial growth factor/ vascular endothelial growth factor receptor axis or multikinase inhibitors. However, a growing body of evidence is pointing out the role of different classes of enzymes involved in tumor-driven angiogenesis, whose inhibition in preclinical models has already shown encouraging results. This review provides an overview on the current knowledge of potential enzymatic targets involved in tumor-driven angiogenesis and the potential clinical applications deriving from their modulation. Metalloproteinase and nitric oxide synthase inhibitors have been found to be, respectively, inefficacious or unsuitable for clinical applications. Conversely, early clinical studies evaluating the inhibition of heparanase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, lysyl oxidase (LOX) and angiotensin-converting enzyme (ACE) have shown promising results. Therefore, preliminary evidence indicates that heparanase, NADPH oxidase, LOX and ACE might represent potential targets for anticancer therapy.