Oncotarget

Priority Research Papers:

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Gemma Shay, Marilena Tauro, Fulvio Loiodice, Paolo Tortorella, Daniel Sullivan, Lori Hazlehurst and Conor C. Lynch _

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Oncotarget. 2017; 8:41827-41840. https://doi.org/10.18632/oncotarget.18103

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Abstract

Gemma Shay1, Marilena Tauro1, Fulvio Loiodice2, Paolo Tortorella2, Daniel M. Sullivan3, Lori A. Hazlehurst4 and Conor C. Lynch1

1 Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

2 Department of Pharmacy and Pharmaceutical Sciences, Università degli Studi di Bari “A. Moro”, Bari, Italy

3 Blood and Marrow Transplantation and Cellular Immunology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

4 Hematopoietic Malignancy and Transplantation Program, West Virginia University, Morgantown, WV, USA

Correspondence to:

Conor C. Lynch, email:

Keywords: bone marrow microenvironment, multiple myeloma, skeletal malignancies, matrix metalloproteinases, bone targeted MMP inhibitors

Received: February 09, 2017 Accepted: April 27, 2017 Published: May 23, 2017

Abstract

Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow of myeloma patients. These data provide rationale for selectively inhibiting MMP-2 activity as a multiple myeloma treatment strategy. Given that MMP-2 is systemically expressed, we used novel “bone-seeking” bisphosphonate based MMP-2 specific inhibitors (BMMPIs) to target the skeletal tissue thereby circumventing potential off-target effects of MMP-2 inhibition outside the bone marrow-tumor microenvironment. Using in vivo models of multiple myeloma (5TGM1, U266), we examined the impact of MMP-2 inhibition on disease progression using BMMPIs. Our data demonstrate that BMMPIs can decrease multiple myeloma burden and protect against cancer-induced osteolysis. Additionally, we have shown that MMP-2 can be specifically inhibited in the multiple myeloma-bone microenvironment, underscoring the feasibility of developing targeted and tissue selective MMP inhibitors. Given the well-tolerated nature of bisphosphonates in humans, we anticipate that BMMPIs could be rapidly translated to the clinical setting for the treatment of multiple myeloma.


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