Gregg L. Semenza

We have cloned and characterized hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. HIF-1 expression increases exponentially as cellular O2 concentration declines. HIF-1 is required for embryonic development of the circulatory system. In postnatal life, HIF-1 activates the transcription of genes that are essential for adaptive responses to hypoxia, such as glycolysis, erythropoiesis, and angiogenesis. We are presently investigating the role of HIF-1 in the pathophysiology of cancer and cardiovascular disease, which are the major causes of mortality in the U.S. population. We have demonstrated that aging and diabetes inhibit HIF-1 activity, thereby blocking ischemia induced angiogenesis. We have constructed an adenoviral vector encoding a constitutively active form of HIF-1 and demonstrated that it can stimulate vascularization of ischemic tissue and thereby overcome the effects of aging and diabetes. We have identified several drugs that potently inhibit HIF-1 activity and block the growth and vascularization of human tumor xenografts in nude mice. Clinical trials to test these agents in cancer patients are currently being organized.