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. Moreover, we build the research proposed here on the results from last year's NSU President's Award.
Porphyromonas gingivalis (P.g.) possesses strong proteolytic activity. We have already shown that endothelial cells are targeted by this activity. Even more important, we 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. We hypothesize that the ability of P.g. proteases to disrupt the junctional bonds could be of considerable importance in suppressing abnormal neovascularization during tumor growth. Our previous data, including the results from the 2003 PFRDG need now to be extended with in vivo experiments, i.e. using animal tumor models. The results of these studies will as usual be presented at national/international meetings and most importantly will serve as necessary foundation for grant support applications with NIH/National Cancer Institute and American Cancer Society.