Failure of matrix metalloproteinase (MMP) inhibitors in cancer clinical trials has been attributed to the broad spectrum nature of the inhibitors, and current efforts are focused on designing specific inhibitors to target individual members of the 20+ family of enzymes. The development of more specific inhibitors has been hampered, however, by the incomplete characterization of the activity of the MMP family members during cancer progression, and it remains unclear which MMPs to target and at what disease stage. A comprehensive picture of MMP activity has not been developed due to limitations in current techniques; most methods are labor intensive and suitable only for particular classes of MMPs. Recently, fluorescent peptide substrates have been developed that can measure MMP activity more easily and specifically. My work focuses on development of a library of multicolor fluorescent peptide biosensors to comprehensively characterize activity of MMPs. To investigate how MMP activity changes in normal and malignant cells, the peptide biosensors have been incorporated into a synthetic extracellular matrix mimic that allows measurement of MMP activity in space and time. Development of this library of peptide biosensors will provide a valuable tool box for the field to rapidly characterize MMP activity during cancer progression, providing data for specific MMPs to target for drug inhibition.
Human mesenchymal stem cells migrating in a PEG hydrogel. Cell mediated degradation causes quenched collagenase sensitive peptide within the gel to fluoresce green.