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
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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.
