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A new approach to anti-angiogenesis therapy.
:: 22 March, 2007
Researchers at Boston University Medical Campus have for the first time identified an enzyme known as Casitas B-lineage lymphoma (c-Cbl) that is activated by VEGF receptor 2. Activated c-Cbl binds to and suppresses enzymatic activity of enzyme known as Phospholipase C-gamma1 (PLC1) and of growth of new blood cells (angiogenesis). The study appears in the online early edition of the Proceedings of the National Academy of Sciences.
Angiogenesis plays a central role in many diseases, from the growth of malignant tumors to the loss of vision associated with diabetic eye disease or macular degeneration. The molecule known to play central role in the development of these abnormal vessels is vascular endothelial growth factor (VEGF).
In order for VEGF to initiate the growth of blood vessels, it must first bind to a specific site on the cells that form the blood vessel wall. These sites are called VEGF receptors. Once VEGF is produced by diseased tissue, it binds to a cell surface receptor known as VEGF-receptor-2 (VEGFR-2). Until now, much of what happens after this point, which leads to proliferation of new blood vessels has been unknown.
Several years ago, these same researchers showed that activation of the enzyme PLC-gamma1 is essential for VEGF to promote angiogenesis. Now, they have shown that c-Cbl antagonizes angiogenesis by promoting ubiquitination of PLC-gamma 1 and suppression of its tyrosine phosphorylation. “Ubiquitination is known to be the kiss of death for a protein. Once a target protein is tagged with ubiquitin, it is destined for degradation,” said senior author Nader Rahimi, PhD, an associate professor at Boston University.
According to Rahimi this work is important because it reveals, for the first time, that c-Cbl suppresses angiogenesis by promoting ubiquitination of PLC-gamma1. “This finding provides a basis for developing a new approach to anti-angiogenesis therapy whether for cancer, or other conditions such as AMD and diabetic retinopathy. The mechanism described in this paper for inhibition of angiogenesis at the level of PLC-gamma 1 and c-Cbl raises the possibility that drugs designed to target these proteins could also be used to treat angiogenesis-associated diseases,” he adds.
About Angiogenesis :
Angiogenesis refers to the process of new blood vessel formation. When tissues need more oxygen, they release molecules that encourage blood vessel growth. Tumors also utilize this same process to enhance their own blood supply in order to nourish their aberrant growth. Genentech scientists, led by Napoleone Ferrara, were the first to prove that inhibition of angiogenesis could starve tumors of their blood supply and inhibit tumor growth.
Ferrara and his team identified the gene for vascular endothelial growth factor (VEGF) more than 15 years ago. They characterized the VEGF protein as the major regulator of physiologic angiogenesis in embryonic development, reproductive biology, endochondral bone formation, and wound repair. In addition, they demonstrated that VEGF is a key mediator of pathologic angiogenesis in certain tumors and ocular disease. These studies led to the development of a humanized anti-VEGF antibody, Avastin® (bevacizumab), as a therapy for solid tumors. Avastin received U.S. Food and Drug Administration approval in February 2004 for use in combination with intravenous 5-Fluorouracil-based chemotherapy as a treatment for first-line metastatic colorectal cancer and in October 2006 for use in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer. In 2005, positive Phase III clinical data were also reported for Avastin in metastatic breast cancer. A related anti-VEGF antibody fragment, LUCENTIS®(ranibizumab injection), also demonstrated clinical benefit in patients with the wet form of age-related macular degeneration. In June 2006, LUCENTIS was approved by the FDA for the treatment of neovascular (wet) age-related macular degeneration.
Media contact:
For Release Upon Receipt - March 19, 2007
Contact: Gina M. Digravio, 617-638-8491, gina.digravio@bmc.org
Release link: http://www.bu.edu/phpbin/news/releases/display.php?id=1291
Tags: Angiogenesis , blood vessel formation , endochondral bone formation , C-gamma1 , vascular endothelial , ,
