Phase III clinical trials with
cancer patients with the first generation of synthetic
MMP inhibitors (MMPIs) failed due to inefficacy and adverse side effects. These results were unexpected, given the wealth of pre-clinical data implicating
MMPs as
cancer targets, but are attributable to the broad-spectrum activity of these early MMPIs and the limited knowledge of the variety of biological functions of
MMPs at the time they were deployed. These experiences stimulated the development of a variety of highly specific synthetic MMPIs. However, the bottle-neck is the identification of true target-
MMPs. Functional genetic approaches are being complicated by the existence of the '
protease web,' i.e., the dynamic interconnectivity of
MMPs and other
proteases, their inhibitors, and substrates that collectively establish homeostasis in signaling in healthy and disease-afflicted tissue. Therefore, even specific
MMP inhibition can result in seemingly unpredictable induction of systemic
protease web-associated modulations (spam), which can comprise
metastasis-promoting molecules such as other
proteases and
cytokines. Such undesired information in local proteolytic networks or relayed systemically in the organism via the proteolytic internet needs to be understood and defined in order to design specific
metastasis therapies employing highly specific MMPIs in combination with spam-filtering agents.