Download anti-proliferative effects of small molecule inhibitors ZM44739, VX680

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.