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The use of RTEF-1, a novel VEGF stimulator, for the treatment of abnormal angiogenesis (BIDMC 799)
Category: Drug Discovery Tools
KeyWords: Angiogenesis; Cancer; Drug Target;
BIDMC ID: 799
Abstract:
Background:
The growth of new blood vessels is a complex process involving the disruption of vascular basement membranes, the migration and proliferation of endothelial cells, and the subsequent formation and maturation of blood vessels. In cases where there is excessive or insufficient angiogenesis, various pathological disorders arise including ischemic myocardia, psoriasis, and peripheral vascular conditions.
Several mediators are known to regulate angiogenesis and the administration of such mediators has been proposed as therapies to either promote or reduce vascularization for the treatment of angiogenic disorders. Given that its receptor is expressed almost exclusively on vascular endothelial cells, vascular endothelial growth factor (VEGF) is one of the most promising angiogenic ligands targeted for therapeutic purposes. Other polypeptides known to influence angiogenesis are fibroblast growth factor (FGF) and, more recently, cyclooxygenase-2 (COX-2).
The ability to specifically regulate angiogenesis, however, remains a significant challenge. The half-life of VEGF, e.g., is extremely short and administration of high doses of the protein is often associated with hypotension. Furthermore, systemic administration of VEGF can cause the induction of angiogenesis in host tissues resulting in blindness, increased aggressiveness of tumor cells, and a multitude of other negative side effects. There therefore exists a need for an effective method of both inducing and inhibiting angiogenesis in a target tissue.
The present invention is based on the inventors? discovery that Hypoxia-induced Related Transcriptional Enhancer Factor-1 (RTEF-1) binds to the promoter regions of VEGF, the Fibroblast Growth Factor Receptor (FGFR) and COX-2, inducing the expression of VEGF, FGFR, and COX-2, respectively. The methods and compositions of this invention are directed to treat, reduce, or prevent conditions caused by hypoxia, and can be used to either promote or inhibit angiogenesis. Also disclosed are screening methods useful for the identification of candidate compounds for increasing or decreasing angiogenesis.
Inventor: Jian Li M.D, Ph.D.
Jue-Lon Shie Ph.D.
Roger J. Laham M.D.
Commercial Opportunity:
The Ischemia Research and Education Foundation reports 25 million patients annually are at risk for perioperative ischemic complications including myocardial infarction, stroke, and renal failure. Of these, approximately 8% or 2 million patients suffer such complications, costing $40 billion annually.
The methods of the present invention are directed to the treatment, reduction, or prevention of ischemic conditions including cardiac infarction, chronic coronary ischemia, chronic lower limb ischemia, stroke, cerebral ischemia, peripheral vascular disease, and myocardial ischemia. Consequently, a patient may be provided with the compositions of the invention in anticipation of an ischemic condition, such as a surgical procedure or trauma.
Competitive Advantages:
Because RTEF-1 controls the expression of three proteins involved in angiogenesis and cardiac function; namely, VEGF, FGFR and COX-2, targeting RTEF-1 would be more effective than other single gene or protein therapies and could potentially provide a treatment for hypoxic and ischemic conditions in addition to any condition that may have endothelial dysfunction or lack of adequate blood flow.
Related Publications:
? J Biol Chem. 2004 Jun 11;279(24):25010-6. Epub 2004 Apr 08. RTEF-1, a novel transcriptional stimulator of vascular endothelial growth factor in hypoxic endothelial cells. Shie JL, Wu G, Wu J, Liu FF, Laham RJ, Oettgen P, Li J. http://www.jbc.org/cgi/content/abstract/279/24/25010
? Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2420-9. Epub 2003 Jul 24. Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF.Wu G, Mannam AP, Wu J, Kirbis S, Shie JL, Chen C, Laham RJ, Sellke FW, Li J. http://ajpheart.physiology.org/cgi/content/abstract/285/6/H2420
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