An antiangiogenic approach is among the most promising avenues in cancer treatment. Current antiangiogenic strategies have focused on compounds that block the ability of the endothelial cells (EC) to break down the surrounding extracellular matrix, that inhibit normal EC directly, or that block factors that stimulate angiogenesis or specifically target integrins to block them or deliver agents to. However, no strategy utilizing degradation of cell adhesion or junctional molecules has yet been reported. The present approach - specific proteolytic targeting of junctional molecules in neovasculature - offers a novel avenue for cancer drug development that is supported by our data as well experimental data from other labs.
Porphyromonas gingivalis (P.g.) possesses strong proteolytic activity. We have already shown (see below) that E-cadherin, occludin and b1-integrin are targeted by this activity in endothelial cells. Even more important, our data showed the decrease of the polarized cell layer integrity to be significantly faster from the basolateral side than from the lumenal side. These data led us to consider the importance of junctional proteins in the maintenance of vascular homeostasis. The focus of our attention is bacterial protein's effect against defined molecular targets, junctional molecules and surface receptors that have a role in cell survival. In particular we hypothesize that the ability of P.g. proteolytic factor to disrupt the junctional bonds could be of considerable importance in suppressing abnormal neovascularization during tumor growth. To further study the effect of this factor on endothelia, and as a last step before in vivo models, the P.I is hereby requesting funds to examine specific in vitro models of angiogenesis, endothelial migration and tube formation inhibition. The results of these studies will as usual be presented at national meetings and most importantly will serve as necessary foundation for grant support applications with National Cancer Institute and American Cancer Society.