title: In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma.
abstract: Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated. In order to better define the effect of an anti-Dkk1 neutralizing Ab on osteoclastogenesis and myeloma, we studied a novel anti-Dkk1 monoclonal Ab in our preclinical models. In vivo data confirmed the pro-anabolic and anti-MM effect. In vitro data in part confirmed the in vivo observation, suggesting an indirect anti-MM effect secondary to inhibition of osteoclastogenesis and thus the interaction between MM and bone microenvironment. However, when studies on osteoclastogenesis were extended to samples derived from MM patients, we observed a variable response to anti-Dkk1 treatment without correlation to expression of surface receptors for Dkk1 in OCs suggesting potential heterogeneity in the efficacy of such a strategy. In conclusion, Dkk1 is a promising target for the treatment of both MM and bone disease, and ongoing clinical studies will help elucidate its efficacy.
authors: Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors: Samantha
authors: S
authors: Pozzi
authors: Mariateresa
authors: M
authors: Fulciniti
authors: Hua
authors: H
authors: Yan
authors: Sonia
authors: S
authors: Vallet
authors: Homare
authors: H
authors: Eda
authors: Kishan
authors: K
authors: Patel
authors: Loredana
authors: L
authors: Santo
authors: Diana
authors: D
authors: Cirstea
authors: Teru
authors: T
authors: Hideshima
authors: Linda
authors: L
authors: Schirtzinge
authors: Stuart
authors: S
authors: Kuhstoss
authors: Kenneth C
authors: KC
authors: Anderson
authors: Nikhil
authors: N
authors: Munshi
authors: David
authors: D
authors: Scadden
authors: Henry M
authors: HM
authors: Kronenberg
authors: Noopur
authors: N
authors: Raje
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D057134:Antibodies, Neutralizing; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins