Abstract
Abstract The European research project Kids Cancer Kinome (KCK) is focusing on the investigation of aggressive childhood cancers. The competence of nine research centers is combined to explore the human protein kinase family in different highly malignant pediatric tumors (medulloblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, ALL) to validate novel drug targets and develop novel therapeutic options. Medulloblastomas belong to the most frequent malignant brain tumors in children and represent about 20% of all pediatric CNS cancers. Analyzing mRNA expression profiles (Affymetrix microarrays) we discovered a series of kinases considerably overexpressed in primary medulloblastoma tumors samples and medulloblastoma cell lines compared to non-neoplastic tissues. We found a significant mRNA overexpression of PLk1 and Aurora kinases A and B in medulloblastoma tumor samples and cell lines. For further investigation we selected these kinases which are all involved in cell cycle control. Defects in the process of cell division are believed to be associated with tumorigenesis. Using the small molecules inhibitors ZM447439 and VX680 for Aurora kinases and BI2536 and GW843682 for PLK1 inhibition we evaluated the effects on medulloblastoma cell proliferation and apoptosis. Incubation of medulloblastoma cells with the inhibitors for 72h resulted in a concentration dependent decrease of the proliferative activity as measured by MTS proliferation assays and an increased apoptosis determined by Caspase-Glo 3/7 assay. In a second approach, we transduced cell lines with lentiviral particles carrying shRNA targeting PLK1 or Aurora kinases A and B. The specific downregulation of the kinases mediated by the lentiviral shRNA was confirmed by Western blotting and had a negative effect on the viability of the medulloblastoma cells. We observed that the effect of PLK1 inhibition on the proliferation of the medulloblastoma cell lines was more effective compared to the aurora kinases. In conclusion, these data suggest that the inhibition of PLK1 or Aurora kinases may represent a promising approach for novel targeted strategies in the treatment of medulloblastoma. http://www.kidscancerkinome.org Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2588. doi:10.1158/1538-7445.AM2011-2588
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