Is there new hope for therapeutic matrix metalloproteinase inhibition?

Key Points Despite promising preclinical data supporting the blockage of MMPs as a treatment for cancer, all Phase III cancer trials failed. This might be due to inadequate clinical trial design, the characteristics of the MMP inhibitors used, poor knowledge on the complexity of the MMPs and discrepancies between the mouse models and the patients enrolled in the clinical trials. Over the past decade, much knowledge has been accumulated on the functions of the different MMPs, and better and more specific MMP inhibitors have been developed. So far, however, this has not resulted in MMP inhibitors that are ready for clinical use. The reluctance to therapeutically inhibit MMPs has been influenced by the failure of the first clinical trials and the observed side effects, the complexity of the MMPs that exert both detrimental and beneficial roles and the lack of tools to dissect the role of a specific MMP in a specific organ. In addition, the high homology between the MMPs, the difficulty in identifying substrate specificity and the discrepancy between in vitro and in vivo identified substrates impede the development of specific MMP inhibitors. Nevertheless, many data are available from studies of MMP-knockout mice and on the use of MMP inhibitors in animals that support therapeutic MMP inhibition in inflammatory conditions such as systemic inflammatory response syndrome (SIRS), sepsis and disorders associated with intestinal and brain inflammation. Based on the currently available data, MMP inhibition has great therapeutic potential for the treatment of inflammatory disorders. However, this can only be fully explored once the MMP functions are unravelled in more detail and potent and selective MMP inhibitors are available. The failure of many clinical trials of the pioneering matrix metalloproteinase (MMP) inhibitors in oncology owing to lack of efficacy and side effects, such as musculoskeletal toxicity, reduced enthusiasm for further development of the drug class. Vandenbroucke and Libert discuss how greater knowledge of MMP biology, as well as the development of more specific MMP inhibitors, could provide new opportunities to use such agents in the treatment of sepsis and other inflammatory disorders. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initi