[en] Inhibition of specific matrix metalloproteinases (MNIP) is an attractive noncytotoxic approach to cancer therapy. MMP-14, a membrane-bound zinc endopeptidase, has been proposed to play a central role in tumor growth, invasion, and neovascularization. Besides cleaving matrix proteins, MMP-14 activates proMMP-2 leading to an amplification of pericellular proteolytic activity. To examine the contribution of MMP-14 to tumor growth and angiogenesis, we used DX-2400, a highly selective fully human MMP-14 inhibitory antibody discovered using phage display technology. DX-2400 blocked proMMP-2 processing on tumor and endothelial cells, inhibited angiogenesis, and slowed tumor progression and formation of metastatic lesions. The combination of potency, selectivity, and robust in vivo activity shows the potential of a selective MMP-14 inhibitor for the treatment of solid tumors. [Cancer Res 2009;69(4):1517-26]
Itoh Y, Seiki M. MT1-MMP: a potent modifier of pericellular microenvironment. J Cell Physiol 2006;206: 1-8.
Li XY, Ota I, Yana I, Sabeh F, Weiss SJ. Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase. Mol Biol Cell 2008;19: 3221-33.
Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett 1996;393:101-4.
Holmbeck K, Bianco P, Caterina J, et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 1999;99:81-92.
Ogura S, Ohdaira T, Hozumi Y, Omoto Y, Nagai H. Metastasis-related factors expressed in pT1 pN0 breast cancer: assessment of recurrence risk. J Surg Oncol 2007;96:46-53.
Rozanov DV, Savinov AY, Williams R, et al. Molecular signature of MT1-MMP: transactivation of the downstream universal gene network in cancer. Cancer Res 2008;68:4086-96.
Tsunezuka Y, Kinoh H, Takino T, et al. Expression of membrane-type matrix metalloproteinase 1 (MT1-MMP) in tumor cells enhances pulmonary metastasis in an experimental metastasis assay. Cancer Res 1996;56:5678-83.
Chun TH, Sabeh F, Ota IJ, et al. MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix. J Cell Biol 2004;167:757-67.
Jiang WG, Davies G, Martin TA, et al. Expression of membrane type-1 matrix metalloproteinase, MT1-MMP in human breast cancer and its impact on invasiveness of breast cancer cells. Int J Mol Med 2006;17:583-90.
Tetu B, Brisson J, Wang CS, et al. The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis. Breast Cancer Res 2006;8:R28.
Mimori K, Ueo H, Shirasaka C, Mori M. Clinical significance of MT1-MMP mRNA expression in breast cancer. Oncol Rep 2001;8:401-3.
Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002;295:2387-92.
Sato H. [Tumor metastasis and MMP inhibitor]. Clin Calcium 2006;16:621-6.
DrummondAH,BeckettP,BrownPD,etal. Preclinical and clinical studies of MMP inhibitors in cancer. Ann N Y Acad Sci 1999;878:228-35.
Skiles JW, Gonnella NC, Jeng AY. The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors. Curr Med Chem 2004;11:2911-77.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161-74.
Della Porta P, Soeltl R, Krell HW, et al. Combined treatment with serine protease inhibitor aprotinin and matrix metalloproteinase inhibitor Batimastat (BB-94) does not prevent invasion of human esophageal and ovarian carcinoma cells in vivo. Anticancer Res 1999;19:3809-16.
Kruger A, Soeltl R, Sopov I, et al. Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Cancer Res 2001;61:1272-5.
Hoet RM, Cohen EH, Kent RB, et al. Generation of high-affinity human antibodies by combining donor-derived and synthetic complementarity-determining- region diversity. Nat Biotechnol 2005;23:344-8.
Jostock T, Vanhove M, Brepoels E, et al. Rapid generation of functional human IgG antibodies derived from Fab-on-phage display libraries. J Immunol Methods 2004;289:65-80.
Morrison JF. Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors. Biochim Biophys Acta 1969;185:269-86.
Copeland RA. Determination of serum protein binding affinity of inhibitors from analysis of concentration-response plots in biochemical activity assays. J Pharm Sci 2000;89:1000-7.
Guo Y, Higazi AA, Arakelian A, et al. A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo. FASEB J 2000;14:1400-10.
Maquoi E, Frankenne F, Noel A, Krell HW, Grams F, Foidart JM. Type IV collagen induces matrix metal-loproteinase 2 activation in HT1080 fibrosarcoma cells. Exp Cell Res 2000;261:348-59.
Mace KA, Hansen SL, Myers C, Young DM, Boudreau N. HOXA3induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair. J Cell Sci 2005;118:2567-77.
Toth M, Gervasi DC, Fridman R. Phorbol ester-induced cell surface association of matrix metallopro-teinase-9 in human MCF10A breast epithelial cells. Cancer Res 1997;57:3159-67.
Sounni NE, Devy L, Hajitou A, et al. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 2002;16:555-64.
Noel A, Hajitou A, L'Hoir C, et al. Inhibition of stromal matrix metalloproteases: effects on breast-tumor promotion by fibroblasts. Int J Cancer 1998;76:267-73.
Sounni NE, Janssen M, Foidart JM, Noel A. Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. Matrix Biol 2003;22:55-61.
Van Meter TE, Broaddus WC, Rooprai HK, Pilkington GJ, Fillmore HL. Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas. Neuro Oncol 2004;6:188-99.
Barbolina MV, Adley BP, Ariztia EV, Liu Y, Stack MS. Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression. J Biol Chem 2007;282:4924-31.
Maquoi E, Sounni NE, Devy L, et al. Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimi-dine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor. Clin Cancer Res 2004;10:4038-47.
Basile JR, Holmbeck K, Bugge TH, Gutkind JS. MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D. J Biol Chem 2007;282:6899-905.
Arroyo AG, Genis L, Gonzalo P, Matias-Roman S, Pollan A, Galvez BG. Matrix metalloproteinases: new routes to the use of MT1-MMP as a therapeutic target in angiogenesis-related disease. Curr Pharm Des 2007;13:1787-802.
Chi A, Norden AD, Wen PY. Inhibition of angiogen-esis and invasion in malignant gliomas. Expert Rev Anticancer Ther 2007;7:1537-60.
Yang X, Dong Y, Zhao J, et al. Increased expression of human macrophage metalloelastase (MMP-12) is associated with the invasion of endometrial adenocarcinoma. Pathol Res Pract 2007;203:499-505.
Gutierrez-Fernandez A, Inada M, Balbin M, et al. Increased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8). FASEB J 2007;21:2580-91.
Zhou Z, Apte SS, Soininen R, et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci U S A 2000;97:4052-7.
