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Abstract :
[en] BACKGROUND Multiple myeloma (MM) is an hematological malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. Osteolytic bone disease (OBD) is a major feature of myeloma, which leads to pathological fractures and hypercalcemia and affects dramatically the morbidity and mortality of patients. Bisphosphonates are the mainstay therapy of MM bone disease; though they are partially effective and related to adverse effects. Research for new therapeutic approaches are of great interest. OBJECTIVES Inhibition of the kinases SRC and MELK were evaluated as treatment of OBD. In addition, the role of galectin-1 (gal-1) in osteoclast (OCL) biology was investigated. RESULTS SRC inhibition by saracatinib inhibited in vitro OCL formation and function and affected osteoblast (OBL) activity. Saracatinib induced in vivo a high reduction of bone loss through the inhibition of bone resorption. Of note, MM cell proliferation and tumor burden remained unaltered following saracatinib treatment. // MELK inhibition by OTSSP167 inhibited OCL activity by decreasing progenitor viability as well as via a direct anti-resorptive effect on mature OCLs. In addition, OTSSP167 stimulated OBL function. This combined anti-resorptive and OBL-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in vivo. // MM-bearing gal-1-/- mice showed higher tumor infiltration and reduced survival compared to wild-type mice. Microarray data analysis revealed a decrease of gal-1 expression during OCL formation, which was confirmed by in vitro OCL cultures. Gal-1-/- OCL cultured ex vivo caused higher bone resorption. Lastly, MM cells-OCLs co-cultures induced a stronger decrease of gal-1 expression in mature OCLs. CONCLUSIONS This thesis indicated SRC and MELK inhibition as promising therapeutic strategies for the treatment of myeloma OBD. Highlighting the implication of gal-1 in OCL biology and MM development warrants further investigation.
