The ADAMs: New Therapeutic Targets for Cancer?

Abstract

The ADAMs are transmembrane proteins implicated in a variety of biological processes including proteolysis, cell signalling, angiogenesis, cell migration, and cell adhesion. Of the 21 ADAMs believed to be functional in humans, approximately one half have been shown to possess protease activity. As proteases, the main ADAM substrates are the ectodomains of transmembrane proteins, especially growth factor precursors, growth factor receptors, and adhesion proteins. Recently, several different ADAMs have been shown to play a role in cancer formation and progression. These include ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, and ADAM28. Consistent with a causative role in cancer, several ADAMs, especially ADAMs 10 and 17, are emerging as potential therapeutic targets for cancer treatment. Indeed, targeting these ADAMs with either low molecular weight inhibitors or monoclonal antibodies has been shown to have anticancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents are unknown.