Abstract
Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest. The proto-oncogene SRC is an attractive target for such a strategy. In the current study, we investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models. In vitro data showed an inhibitory effect of saracatinib on osteoclast differentiation, polarization and resorptive function. In osteoblasts, collagen deposition and matrix mineralization were affected by saracatinib. MM cell proliferation and tumor burden remained unaltered following saracatinib treatment and we could not detect any synergistic effects with drugs that are part of standard care in MM. We observed a marked reduction of bone loss after treatment of MM-bearing mice with saracatinib as reflected by a restoration of trabecular bone parameters to levels observed in naive control mice. Histomorphometric analyses support that this occurs through an inhibition of bone resorption. In conclusion, these data further establish SRC inhibition as a promising therapeutic approach for the treatment of MM-associated osteolytic bone disease.
Highlights
Multiple myeloma (MM) is the second most common hematological malignancy and accounts for approximately 1% of all cancers and 2% of all deaths from cancer
Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest
We investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models
Summary
Multiple myeloma (MM) is the second most common hematological malignancy and accounts for approximately 1% of all cancers and 2% of all deaths from cancer. MM is characterized by the clonal proliferation and accumulation of malignant plasma cells in the bone marrow (BM), monoclonal serum protein and associated organ dysfunction [2]. A major cause of morbidity and mortality in MM is the development of bone destructive lesions due to osteolytic bone disease, which occurs in more than 80% of MM patients. MMassociated osteolytic bone disease is characterized by increased osteoclastogenesis and suppression of osteoblast function This occurs via multiple mechanisms, including the secretion of osteoclastogenic factors and osteoblastinhibitory factors by both MM cells and stromal cells in the MM microenvironment. We investigated the effect of saracatinib on osteoclast and osteoblast function, and on the development of MM and its associated osteolytic bone disease
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