Lenalidomide in combination with an activin A-neutralizing antibody: Preclinical rationale for a novel anti-myeloma strategy

T. Scullen, L. Santo, S. Vallet, M. Fulciniti, H. Eda, D. Cirstea, K. Patel, N. Nemani, A. Yee, A. Mahindra, N. Raje*

*Korrespondierende:r Autor:in für diese Arbeit

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

43 Zitate (Scopus)

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.

OriginalspracheEnglisch
Seiten (von - bis)1715-1721
Seitenumfang7
FachzeitschriftLeukemia
Jahrgang27
Ausgabenummer8
DOIs
PublikationsstatusVeröffentlicht - Aug. 2013
Extern publiziertJa

ASJC Scopus Sachgebiete

  • Hämatologie
  • Onkologie
  • Krebsforschung

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