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 Blood, 30 April 2009, Vol. 113, No. 18, pp. 4331-4340.
Prepublished online as a Blood First Edition Paper on January 26, 2009; DOI 10.1182/blood-2008-09-178350.

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LYMPHOID NEOPLASIA

Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma

Dirk Hose1,2, Thierry Rème3,4, Tobias Meissner1, Jérôme Moreaux3,4, Anja Seckinger1, Joe Lewis5, Vladimir Benes5, Axel Benner6, Michael Hundemer1, Thomas Hielscher6, John D. Shaughnessy, Jr7, Bart Barlogie7, Kai Neben1, Alwin Krämer1, Jens Hillengass1, Uta Bertsch1, Anna Jauch8, John De Vos3,4, Jean-François Rossi3,4, Thomas Möhler1, Jonathon Blake5, Jürgen Zimmermann5, Bernard Klein3,4, and Hartmut Goldschmidt1,2

1 Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany; 2 Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany; 3 Centre Hospitalier Universitaire (CHU) Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, Montpellier, France; 4 Inserm U847, Montpellier, France; 5 European Molecular Biology Laboratory, Heidelberg, Germany; 6 Abteilung für Biostatistik, Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany; 7 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock; and 8 Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Germany

Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.


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D. Hose, J. Moreaux, T. Meissner, A. Seckinger, H. Goldschmidt, A. Benner, K. Mahtouk, J. Hillengass, T. Reme, J. De Vos, et al.
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