title: The effect of the dual PI3K and mTOR inhibitor BEZ235 on tumour growth and osteolytic bone disease in multiple myeloma.
abstract: The plasma cell malignancy multiple myeloma (MM) is unique among haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt/mTOR pathway mediates proliferation, survival and drug resistance in MM plasma cells and is also involved in regulating the formation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts. NVP-BEZ235 is a dual pan class I PI3K and mTOR inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we examined the anti-tumorigenic effects of BEZ235 in an immunocompetent mouse model of MM and assessed the effects of BEZ235 on osteoblast and osteoclast formation and function. BEZ235 treatment (50 mg/kg) resulted in a significant decrease in serum paraprotein and tumour burden, and μCT analysis of the proximal tibia revealed a significant reduction in the number of osteolytic bone lesions in BEZ235-treated animals. Levels of the serum osteoblast marker P1NP were significantly higher in BEZ235-treated animals, while levels of the osteoclast marker TRAcP5 were reduced. In vitro, BEZ235 decreased MM plasma cell proliferation, osteoclast formation and function and promoted osteoblast formation and function. These findings suggest that, in addition to its anti-tumour properties, BEZ235 could be useful in treating osteolytic bone disease in MM patients.
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, SA; Centre for Stem Cell Research, Robinson Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA.
authors.forename: Zhen Ying
authors.initials: ZY
authors.lastname: Gan
authors.forename: Stephen
authors.initials: S
authors.lastname: Fitter
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
authors.forename: Luen B
authors.initials: LB
authors.lastname: To
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.forename: Sally K
authors.initials: SK
authors.lastname: Martin
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: BEZ235; PI3K; bone; mTOR; multiple myeloma