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Inhibition of Aurora-kinases for tailored risk adapted treatment of multiple myeloma.

Abstract : 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 two independent sets of 233 and 345 CD138-purified myeloma-cells from previously untreated myeloma-patients. Chromosomal aberrations were assessed by comprehensive iFISH and proliferation of primary myeloma-cells by propidium-iodine staining. The effect of the clinical Aurora-kinase inhibitor VX680 on proliferation of 20 human-myeloma-cell-lines and survival of 5 primary myeloma-cell-samples was tested. We found Aurora-A and -B to be expressed at varying frequencies in primary myeloma-cells of different patient-cohorts, Aurora-C in testis-samples only. Myeloma-cell samples with detectable vs. absent Aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations present (aneuploidy) nor of subclonal aberrations (chromosomal instability). VX680 induces apoptosis in all myeloma-cell-line- and primary myeloma-cell-samples tested. Presence of Aurora-A expression delineates significantly inferior event-free and overall-survival in two independent cohorts of patients undergoing high-dose chemotherapy, independent of conventional prognostic factors, i.e. serum-beta2-microglobulin or ISS-stage. In conclusion, using gene expression profiling, Aurora-kinase inhibitors as promising therapeutic option for newly-diagnosed patients can be tailoredly given to patients with adverse prognosis, expressing Aurora-A.
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Submitted on : Monday, March 16, 2009 - 2:55:55 PM
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Dirk Hose, Thierry Rème, Tobias Meissner, Jérôme Moreaux, Anja Seckinger, et al.. Inhibition of Aurora-kinases for tailored risk adapted treatment of multiple myeloma.. Blood, American Society of Hematology, 2009, 113 (18), pp.4331-4340. ⟨10.1182/blood-2008-09-178350⟩. ⟨inserm-00368414⟩



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