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Sydney 2005: Toward the Elucidation of the Role of Altered Wnt Signaling MM
By Erming Tian, MD
Dr. Tian reviewed the clinical data showing that bisphosphonates stop bone lesions but do not repair bone tissue. Examination of the contributions of the DKK1 gene in patients with myeloma bone disease or in normal bone donors showed that normal donors have lower DKK1 levels than myeloma patients, regardless of whether the myeloma patients have active disease. Use of a monoclonal antibody against DKK1 in a mouse model showed that monoclonal antibody inhibition of DKK1 was associated with increased numbers of osteoblasts, reduced number of osteoclasts, reduced bone loss, and reduced tumor burden. The data suggest that DKK1 produced by myeloma cells in the bone marrow contributes to bone defects. Other results suggest that DKK1 promotes myeloma cell proliferation; blocking DKK1 inhibits myeloma tumor growth. Additionally, data show that DKK1 can be activated by genotoxic and non-genotoxic agents in other tumor cells, activated by tumor and non-tumor cells, activated by thalidomide and other drugs, but not activated by proteasome inhibitors (eg, bortezomib). Furthermore, these findings suggest that DKK1 may be the mediator of thalidomide embyropathy.

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