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| Status |
Public on Feb 14, 2018 |
| Title |
Inhibition of the kinesin spindle protein enhances the activity of pomalidomide and dexamethasone in multiple myeloma [In Vitro] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Kinesin spindle protein (KSP) inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (Arry-520), a KSP inhibitor, has demonstrated activity in heavily pretreated multiple myeloma (MM) patients. The aim of this work was to investigate the activity of filanesib in combination with an IMiDs plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. Results: Filanesib showed in vitro and in vivo synergy with all IMiDs plus dexamethasone treatment, particularly with the pomalidomide combination (PDF). Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and it was shown to be mediated by impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, PDF increased the activation of the proapoptotic protein Bax, which has been previously associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Conclusions: Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone and es-tablished the basis for a recently activated trial being conducted by the Spanish MM group investigating this combination in relapsed MM patients.
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| Overall design |
The ability of filanesib to enhance the activity of the different IMiDs plus dexamethasone was compared in several in vitro and in vivo models. Mechanisms of the most synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and siRNA studies
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| Contributor(s) |
Hernández-García S, San-Segundo L, González-Méndez L, Corchete LA, Misiewicz-Krzeminska I, Martín-Sánchez M, López-Iglesias A, Algarín EM, Paíno T, Tunquist B, Mateos M, Gutiérrez NC, Díaz-Rodriguez E, Garayoa M, Ocio EM |
| Citation(s) |
28860344 |
| Submission date |
Jan 31, 2017 |
| Last update date |
Mar 15, 2019 |
| Contact name |
Enrique M. Ocio |
| E-mail(s) |
emocio@usal.es
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| Phone |
+34 923294812
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| Organization name |
Centro de investigación del cáncer
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| Street address |
Campus Universitario Miguel de Unamuno
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| City |
Salamanca |
| State/province |
Salamanca |
| ZIP/Postal code |
37007 |
| Country |
Spain |
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| Platforms (1) |
| GPL16686 |
[HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE94341 |
Inhibition of the kinesin spindle protein enhances the activity of pomalidomide and dexamethasone in multiple myeloma |
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| Relations |
| BioProject |
PRJNA369397 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE94334_RAW.tar |
99.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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