Abstract B07: Targeting an MT1-MMP/MMP2 axis in melanoma by a novel MT1-MMP/MMP2 inhibitor

Abstract

Abstract Metastatic melanoma remains the deadliest of all skin cancers with a survival rate at five years of less than 15%. Matrix metalloproteases (MMPs) are among the proteolytic enzymes responsible for the degradation/ digestion of the extracellular matrix (ECM) and have been associated with the aggressiveness of a variety of cancers including melanoma (1,2). MT1-MMP is a membrane associated matrix metalloproteinase that controls pericellular proteolysis and is an important, invasion-promoting, pro-tumorigenic MMP in cancer. We have recently demonstrated that MT1-MMP plays a key role in melanoma metastasis (3). MT1-MMP expression increases with disease progression and is associated with poor melanoma patient outcome, underscoring a pivotal role of MT1-MMP in melanoma pathogenesis. Indeed, we showed that MT1-MMP is required for melanoma cells to metastasize, as cells deprived of MT1-MMP fail to form distant metastasis in an orthotopic mouse melanoma model. Mechanistically, we demonstrated for the first time that MT1-MMP affects cell invasion and motility by activating an MMP2-RAC1 signaling axis in melanoma cells (3). These findings imply MT1-MMP/MMP2 represent good molecular targets to thwart melanoma metastasis. However, the targeting of MMPs has not met with very successful stories mostly because the use of broad-spectrum inhibitors have been accompanied by severe side effects, such as musculoskeletal pain and inflammation (4,5) due to the targeting of both the “good” and the “bad” MMPs (6-8). Here we present new data in support of a novel, specific MT1-MMP/MMP2 inhibitor. ND-322 is a slow binding selective inhibitor of MT1-MMP and MMP2 (9). Data in our laboratory indicate ND-322 inhibits cell growth, migration and invasion of several melanoma cell lines similarly to the knock down of MT1-MMP and/or MMP2; it decreases RAC1 activity; and importantly, significantly reduces in vivo tumor growth and metastasis in an orthotopic mouse melanoma model. Preliminary data in vitro also show ND-322 in combination with vemurafenib decreases melanoma cell viability in a synergistic manner. Given these results and considering that this compound is very well tolerated in vivo (10), we believe ND-322 represent a promising novel, safe addition to the current standard of care for melanoma patients with advanced disease. Literature Cited 1 Bartolome, R.A., Ferreiro, S., Miquilena-Colina, M.E., Martinez-Prats, L., Soto- Montenegro, M.L., Garcia-Bernal, D., Vaquero, J.J., Agami, R., Delgado, R., Desco, M., Sanchez-Mateos, P., & Teixido, J. Am J Pathol 174 (2), 602-612 (2009). 2 Moro, N., Mauch, C., & Zigrino, P. Eur J Cell Biol 93 (1-2), 23-29 (2014). 3 Shaverdashvili k., W.P., Ma J., Zhang K., Osman I., Bedogni B. Pigment Cell and melanoma Res In Press (2013). 4 Skiles, J.W., Gonnella, N.C., & Jeng, A.Y. Curr Med Chem 11 (22), 2911-2977 (2004). 5 Drummond, A.H., Beckett, P., Brown, P.D., Bone, E.A., Davidson, A.H., Galloway, W.A., Gearing, A.J., Huxley, P., Laber, D., McCourt, M., Whittaker, M., Wood, L.M., & Wright, A. Ann N Y Acad Sci 878, 228-235 (1999). 6 Zucker, S. & Cao, J. Cancer Biol Ther 8 (24), 2371-2373 (2009). 7 Hua, H., Li, M., Luo, T., Yin, Y., & Jiang, Y. Cell Mol Life Sci 68 (23), 3853-3868 (2011). 8 Dufour, A. & Overall, C.M. Trends Pharmacol Sci 34 (4), 233-242 (2013). 9 Gooyit, M., Lee, M., Schroeder, V.A., Ikejiri, M., Suckow, M.A., Mobashery, S., & Chang, M. J Med Chem 54 (19), 6676-6690 (2011). 10 Cui, J., Chen, S., Zhang, C., Meng, F., Wu, W., Hu, R., Hadass, O., Lehmidi, T., Blair, G.J., Lee, M., Chang, M., Mobashery, S., Sun, G.Y., & Gu, Z. Mol Neurodegener 7, 21 (2012). Citation Format: Khvaramze Shaverdashvili, Poki Wong, Jun Ma, Keman Zhang, Iman Osman, Barbara Bedogni. Targeting an MT1-MMP/MMP2 axis in melanoma by a novel MT1-MMP/MMP2 inhibitor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B07.