Angiogenesis is the formation of new capillary blood vessels as outgrowths of pre-existing vessels. This tightly regulated process plays a vital role in many physiological processes, such as embryogenesis, wound healing, and menstruation. Angiogenesis is also important in certain pathological events, such as solid tumor growth and metastasis, arthritis, psoriasis, and diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a mitogenic factor that stimulates pro-angiogenic properties, including endothelial cell migration, tube formation and proliferation. The recognition of VEGF as a primary stimulus of angiogenesis in pathological conditions has led to various attempts to block VEGF activity. While blockage of VEGF function is effective in reducing tumor growth, it is not sufficient. This is in part due to the need for an inhibitor that can also block the function of proteases which are responsible for degradation of the ECM, a necessary event for metastases to occur. Angiostatin is a naturally occurring angiogenesis inhibitor. It is a cleavage product of plasminogen, the protein that is converted to plasmin, one protease involved in degradtion of the ECM. Production of angiostatin would limit the amount of plasminogen available for conversion to plasmin. By itself, angiostatin is not an effective angiogenesis inhibitor.
Dartmouth researchers established that a truncated porcine PAI-1 protein, rPAI-123, induces apoptosis in 39% of adherent bovine aortic endothelial cells, inhibits tubule migration by 65% in an organ culture, and blocks the release of heparin-binding VEGF-A isoforms. Our data show that rPAI-123 has two anti-angiogenic functions: (a) blockage of VEGF survival function and (b) induces angiostatin production. The cumulative effect is potent inhibition of angiogenesis.
In vivo studies of a highly invasive breast tumor xenograft model show that rPAI-123 reduces tumor volume by 68%, reduces metastases by 75% and increases apoptosis by 15-fold. The concentration of rPAI-123 required for the in vivo anti-angiogenic effect is 10-3 less than the angiostatin dose. These studies support the in vitro and ex vivo mechanisms that have been reported. The combined effect is a potent angiogenesis inhibitor that is effective at a much lower dose. The protein has a two pronged anti-angiogenic effect: (a) inhibition of VEGF; (b) inhibition of plasmin function in metastatic processes.
This technology is claimed in the issued United States Patents Nos. 7,306,803, 7,241,446 and 7,510,714. We are seeking an industrial partner interested in its commercialization. (Ref: J191, J254)
Last Updated: 7/24/12