When keratinocytes (cells in the skin) become cancerous they can develop into squamous cell carcinoma (SCC), a cancer that develops in many people with recessive dystrophic EB. A molecule called avß6, which is expressed on the surface of normal keratinocytes, allowing them to migrate and to produce factors to repair damaged skin, is significantly expressed on SCC cells. Dr Marshall’s group has shown that this same molecule, avß6, is responsible for the ability of SCC cells to invade. They have found that by inhibiting the ability of avß6 to bind to its target proteins they can inhibit SCC cell invasion. They have also found that they can inhibit partially the ability of the avß6 to instruct the cell to invade by introducing inside cells, small protein fragment that bind to the intra-cellular portion of the avß6. They believe that these small protein fragments are disturbing the normal mechanisms that avß6 molecules use to send messages into the cells.

In the proposed study, they wish to extend their observations in the following ways. Firstly, they wish to generate a panel of cyclic-peptides that can block the ability of avß6 to bind to its normal target. They have been using a commercially available antibody but this product is not suitable for development into a clinically useable drug. The cyclic-peptides that are discovered that have the greatest efficiency would be tests in animals and, hopefully, ultimately in humans. The second target is the intracellular portion of avß6. Although they have identified one novel peptide which appears to suppress SCC cell invasion, the effect is not complete. Therefore, they wish to test other, potentially useful peptides, which may also bind to the cytoplasmic tail of ß6.