title: Lenalidomide in combination with an activin A-neutralizing antibody: preclinical rationale for a novel anti-myeloma strategy.
abstract: Given the prevalence of osteolytic bone disease in multiple myeloma (MM), novel therapies targeting bone microenvironment are essential. Previous studies have identified activin A to be of critical importance in MM-induced osteolysis. Lenalidomide is a known and approved treatment strategy for relapsed MM. Our findings demonstrate that lenalidomide acts directly on bone marrow stromal cells via an Akt-mediated increase in Jun N-terminal kinase-dependent signaling resulting in activin A secretion, with consequent inhibition of osteoblastogenesis. Here, we attempted to augment the antitumor benefits of lenalidomide while overcoming its effects on osteoblastogenesis by combining it with a neutralizing antibody to activin A. Increased activin A secretion induced by lenalidomide was abrogated by the addition of activin A-neutralizing antibody, which effectively restored osteoblast function and inhibited MM-induced osteolysis without negating the cytotoxic effects of lenalidomide on malignant cells. This provides the rationale for an ongoing clinical trial (NCT01562405) combining lenalidomide with an anti-activin A strategy.
authors: Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: T
authors: T
authors: Scullen
authors: L
authors: L
authors: Santo
authors: S
authors: S
authors: Vallet
authors: M
authors: M
authors: Fulciniti
authors: H
authors: H
authors: Eda
authors: D
authors: D
authors: Cirstea
authors: K
authors: K
authors: Patel
authors: N
authors: N
authors: Nemani
authors: A
authors: A
authors: Yee
authors: A
authors: A
authors: Mahindra
authors: N
authors: N
authors: Raje
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D000077269:Lenalidomide; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; C422405:activin A; D028341:Activins; D013792:Thalidomide; D000077269:Lenalidomide