New approaches to selectively target cancer-associated matrix metalloproteinase activity

• Published in: Cancer and metastasis reviews Vol. 33; no. 4; pp. 1043 - 1057
• Main Authors: Tauro, Marilena, McGuire, Jeremy, Lynch, Conor C.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.12.2014; Springer; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinogenesis - drug effects; Cytokines; Development and progression; Extracellular Matrix - drug effects; Health aspects; Humans; Matrix Metalloproteinase Inhibitors - therapeutic use; Matrix Metalloproteinases - biosynthesis; Matrix Metalloproteinases - genetics; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neovascularization, Pathologic; Non-Thematic Review; Oncology; Tumor Microenvironment - drug effects; Extracellular matrix; Cancer progression and metastasis; Matrix metalloproteinase; Tumor microenvironment; Activity-based protein probes
• ISSN: 0167-7659; 1573-7233
• DOI: 10.1007/s10555-014-9530-4

Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.