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Abstract for XVIIth International Congress of Neuropathology, 11-15.09.2010 Salzburg, Austria Targeting overexpressed Aurora kinases in childhood medulloblastoma: anti-proliferative effects of small molecule inhibitors ZM44739, VX680 and shRNA Martin I. Holst1, Ellen Westerhout3, Marcel Kool3, Huib Caron2, Rogier Versteeg2, Steve Clifford4, Stefan Rutkowski5, Torsten Pietsch1 1Department of Neuropathology, University of Bonn, Bonn, Germany Oncology, Emma Children's Hospital AMC, Amsterdam, Netherlands 3Department of Human Genetics, Academic Medical Center, Amsterdam, Netherlands 4Northern Institute for Cancer Research, Newcastle University,The Medical School, Newcastle, UK 5Department of Pediatric Hematology and Oncology, University of Hamburg-Eppendorf, Hamburg, Germany http://www.kidscancerkinome.org 2Pediatric Kids Cancer Kinome (KCK) is a European research project investigating aggressive childhood cancers. Focusing on the human protein kinase family nine research centers explore different highly malignant pediatric tumors (medulloblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, ALL) to validate novel drug targets and develop novel therapeutic options. Medulloblastomas of the cerebellum represent the most frequent malignant brain tumors of childhood. Previous studies revealed Aurora kinase A (STK15) as an independent predictor for an unfavorable outcome of medulloblastoma patients. The Aurora kinases belong to the family of serine/threonine kinases which are involved in the cell cycle by controlling chromatid segregation. It is commonly approved, that defects in the process of cell division are associated with tumorigenesis. Using mRNA expression profiling we compared the Aurora kinase mRNA expression of medulloblastoma tumor samples with normal cerebellar tissue and various other tumor types. We discovered a significant overexpression of Aurora kinase mRNA in primary medulloblastoma tumors and medulloblastoma cell lines compared to nonneoplastic tissues. We evaluated the effects of the Aurora kinase inhibitors ZM447439 and VX680 on the proliferation of medulloblastoma cell lines. Incubation of medulloblastoma cells with ZM447439 and VX680 resulted in a concentration dependent decrease of the proliferative activity. The specific downregulation of the Aurora kinases with lentiviral shRNA had a negative effect on the viability of the medulloblastoma cells. In conclusion, these data suggest that the inhibition of Aurora kinases may represent a promising approach for novel targeted strategies for the treatment of medulloblastoma.