- Enrique M. Ocio1,2⇓,
- David Vilanova1,
- Peter Atadja3,
- Patricia Maiso1,
- Edvan Crusoe1,
- Diego Fernández-Lázaro1,
- Mercedes Garayoa1,
- Laura San-Segundo1,
- Teresa Hernández-Iglesias1,
- Enrique de Álava1,
- Wenlin Shao3,
- Yung-Mae Yao3,
- Atanasio Pandiella1 and
- Jesús F. San-Miguel1,2
- 1 Centro de Investigación del Cáncer, IBMCC/CSIC-Universidad de Salamanca, Spain
- 2 Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- 3 Novartis Institutes for Biomedical Research, Cambridge, MA, USA
- Correspondence: Enrique M. Ocio, Department of Hematology, University Hospital & Cancer Research Center. University of Salamanca Pº San Vicente, 58-182, 37007 Salamanca, Spain. E-mail:
Background Combinations based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. In this manuscript we have explored the antimyeloma activity of the triple combination of these well established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.
Design and Methods The activity of these combinations was explored in vitro in cell lines by using MTT and Annexin V; ex vivo by flow cytometry; and in vivo using two different murine models of human myeloma: one bearing a subcutaneous plasmacytoma and another with a disseminated myeloma. Moreover, gene expression profile and immunohistochemical studies were performed.
Results The addition of panobinostat (LBH589) to dexamethasone and either bortezomib (PBD) or lenalidomide (PLD) resulted in clear potentiation in MM cell lines, freshly isolated plasma cells, and MM murine models. The quantification of the potency of these combinations by using the Chou-Talalay method showed synergistic combination indexes in all of them. This effect derived from the deregulation of a cluster of genes completely different to the sum of genes affected with single agents (895 and 1323 genes exclusively deregulated by PBD and PLD respectively). Functional experiments, such as Annexin V staining, cell cycle analysis, and immunohistochemical studies also supported this potentiation. Anti-myeloma efficacy was confirmed in an extramedullary plasmacytoma model and a disseminated luciferized model, in which panobinostat also provided a marked benefit in bone disease.
Conclusions The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in MM.
- Received August 7, 2009.
- Revision received September 22, 2009.
- Accepted October 13, 2009.
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