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.
Highlights
Multiple myeloma is characterized by the clonal expansion of malignant plasma cells within the bone marrow [1]
Given the possible roles for tumor and bone derived matrix metalloproteinase-9 (MMP)-2 in driving the progression of skeletal malignancies we examined human multiple myeloma biopsies (n = 10) for the presence of Matrix metalloproteinase-2 (MMP-2)
Using immunofluorescence and CD138 to identify the myeloma cells, we observed that the majority of multiple myeloma cells in the bone marrow biopsies were positive for MMP-2 (Figure 1A and 1B)
Summary
Multiple myeloma is characterized by the clonal expansion of malignant plasma cells within the bone marrow [1]. Myeloma cells induce extensive osteolysis via the activation of bone resorbing osteoclasts [2]. Targeting the bone microenvironment represents a logical therapeutic strategy for the treatment of the disease. To this end, bisphosphonates such as zoledronate can bind to the skeleton due to their pyrophosphate analog backbone and induce osteoclast apoptosis during resorption [6]. Given the success of bisphosphonates in the clinic and other agents that modulate the bone microenvironment including denosumab (an inhibitor of the osteoclastogenic factor www.impactjournals.com/oncotarget receptor activator of nuclear κB ligand-RANKL) there is strong rationale for the further development of therapeutics that limit tumor-bone interaction [9]
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