Oral cancer is the sixth most common cancer in the world and characterized by a high degree of local invasiveness and a high rate of metastasis. High level expression and activity of MMP-2, a member of the family of matrix metalloproteinases (MMPs), has been associated with increased tumor expansion and metastasis of oral cancers. The potential utility of MMP inhibitors has therefore lead to significant research in the area. Although several currently available inhibitors are efficient on MMPs, they generally have low specificity for individual MMPs due to the structural similarity of the catalytically active sites among the MMPs. Consequently, clinical cancer trials with such inhibitors have experienced significant clinical side effects due to the non-specific MMP inhibition. While there is little regulation of MMP-2 at the transcriptional level, this enzyme is subject to a unique activation process among the MMPs. MMP-2 activation occurs in a cell membrane-associated complex involving membrane type 1 MMPs (MT1-MMPs), tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and proMMP-2. That addition of excess soluble TIMP-2 added to the activation system inhibits MMP-2 activation points to a possible novel strategy for specific MMP-2 inhibition. The hypothesis of this proposal is that peptides may be identified which block interactions in the activation complex between TIMP-2 and proMMP-2 and thereby inhibit the MMP-2 activities. The experiments are designed to use advanced recombinant protein biochemical and molecular biological approaches to identify inhibitors from random libraries of short peptides. Peptides with the appropriate binding characteristics will be synthesized and tested in vitro and in a cancer cell culture system to determine whether the peptides inhibit the MMP-2 activation and activity, and in turn alter cancer cell behavior. The proposed experiments will generate the information required to pursue the long-term goal which is to explore in detail the structure-function basis of MMP-2 activation and to develop new MMP inhibitors and strategies for use in treatment of oral cancer. Enzymes called MMPs can degrade tissues and are important for progression of oral cancer. This research project will test new approaches to inhibit MMPs. The goal is to develop MMP inhibitors for treatment of oral cancer. ? ? ?
