Angiogenesis and Anti-angiogenic Therapy in Head and Neck Cancer

The formation of new blood vessels, or angiogenesis, takes place through a variety of different physiologic and unique pathologic processes in tumor tissue. While the control mechanisms of some of these processes are not yet understood, as in the case of de novo vessel formation or intussusceptive angiogenesis, a closer examination of the process of sprouting angiogenesis highlights the complexity of the molecular mechanisms of angiogenesis. Through both positive regulation with proteins such as vascular endothelial growth factors (VEGFs), fibroblast growth factor (FGF), and NOTCH and negative regulation with other signals such as thrombospondin, endostatin, and angiostatin, the endothelial cells of an existing vessel can reorganize into new functional luminal architecture. As our comprehension of the regulatory machinery has improved, so has the desire to create anti-angiogenic therapies using targeted monoclonal antibodies, tyrosine kinase inhibitors, and other novel targeted small molecular inhibitors directed at interrupting these regulatory signals. Drugs directed against vascular endothelial growth factors in particular (e.g., bevacizumab or sunitinib) have been studied as antineoplastic agents either alone or in combination with cytotoxic chemotherapy or other targeted agents. A unique toxicity profile has been seen with anti-angiogenics that may include events such as bleeding, hypertension, and proteinuria. The interest in targeting angiogenesis continues, and more clinical trials are underway with new targets and evolving strategies.