| Summary: | <p>Multiple myeloma is a fatal haematological malignancy, in which the majority of patients either present with or develop a destructive and debilitating osteolytic bone disease. The bone disease is characterised by an increase in osteoclastogenesis and by osteoblast suppression. Current treatments for MM bone disease include bisphosphonates and denosumab, both of which act to inhibit osteoclast formation and thus limit bone resorption. Recently the glycosphingolipid inhibitor miglustat was found to be effective in the treatment of myeloma bone disease. Eliglustat is small molecule drug that inhibits glucosylceramide synthase and is approved by the Food and Drug Administration for the treatment of Gaucher's Disease. Patients with Gaucher’s disease have an increased risk of MM development, raising the possibility that this drug may be of benefit in MM. This thesis aimed to investigate the efficacy of eliglustat in myeloma bone disease in vivo, and to determine its mechanism of action.
<p>Preliminary data revealed that treatment with eliglustat in a murine MM model reduced osteolytic bone lesion development, associated with a reduction in osteoclast number but no change in osteoblastic bone formation. Eliglustat was also found to be effective in reducing myeloma bone disease in both diet-induced obesity and ageing models of myeloma. The combination of eliglustat and the bisphosphonate, zoledronic acid, was found to have a greater effect to reduce myeloma bone disease than either agent alone, suggesting the potential for combination therapies that allow for dose reductions. Mechanistic studies demonstrated that Eliglustat is likely to inhibit OC formation via preventing degradation of TRAF3 in OC precursors. This could be achieved either by disrupting GSL integrity in the cell membrane or working as an autophagy inhibitor to exert its effect in OC by maintaining TRAF3 protein level. </p>
<p>Taken together, this project identifies a novel mechanism by which GSL inhibition impacts osteoclastogenesis and highlights the translational potential of eliglustat for the treatment of myeloma bone disease.</p>
|
|---|