Several devastating diseases such as cancer, ocular neovascularization and rheumatoid arthritis are considered angiogenesis-dependent because the progression of these pathologies requires continued neovascularization. The survival, growth and metastasis of solid tumors is directly related to the success of blood vessel ingrowth from surrounding pre-existing vasculature. Stimulation of angiogenic processes associated with ocular neovascularization and rheumatoid arthritis leads to capillary ingrowth into normally avascular tissues causing organ dysfunction or failure. Despite aggressive treatment efforts, current strategies have not been highly successful in reducing or preventing angiogenesis-related disease progression. Recent advances in understanding to the interactions between extracellular matrix and endothelial cells involved in angiogenesis have provided an opportunity selectively inhibit neovascularization using antagonists of cell adhesion molecules known as integrins. Monoclonal antibodies directed against specific integrins, and synthetic RGD-containing peptides that antagonize integrins have been recently shown to inhibit angiogenesis both in vitro and in vivo. Telios Pharmaceuticals, Inc. has synthesized and screened an extensive library of RGD-containing peptides. Based on receptor binding analyses, we have identified a number of compounds that are highly potent and selective for specific or multiple integrin types. We have conducted preliminary experiments and identified certain of these compounds that inhibit angiogenesis in an ex vivo model. In this Phase I study we propose to further characterize these lead compounds using endothelial cell cultures and in situ angiogenesis models. These agents can then be subsequently tested and optimized in animal models in Phase II. Development of a therapeutic agent that selectively inhibits angiogenesis would have tremendous impact on the treatment of angiogenic-dependent disorders. PROPOSED COMMERCIAL APPLICATION: Greater than 800,000 cases of solid tumors are detected each year. Development of a therapeutic agent that inhibits angiogenesis using RGD-containing peptides represents a novel approach to the treatment of angiogenic-dependent diseases and encompasses a large commercial market.
Thesaurus Terms:angiogenesis inhibitor, cell adhesion molecule, drug design /synthesis /production, peptide angiogenesis, disease model, integrin, protein sequence chick embryo, laboratory rat, tissue /cell cultureNational Cancer Institute (NCI)
