The preliminary KCK data have been presented by Huib Caron from AMC at the NCI EORCT AACR meeting (symposium on “Molecular targets and Cancer Therapeutics”) in Geneva in last October 2008.
KidsCancerKinome: a EU-FP6 project for preclinical kinase inhibitor evaluation as a tool to prioritize compounds for paediatric development
KidsCancerKinome will make a comprehensive analysis of the human protein kinase family. Protein kinases are already excellent targets for many small inhibitory molecules and antibodies designed for adult tumours. Six aggressive childhood tumours (neuroblastoma, medulloblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma and acute lymphocytic leukaemia) will be addressed. These six tumours are responsible for 50% of childhood cancer deaths. RNAi knockdown of kinase expression by viral shRNA libraries will be applied to test the human kinase gene family for tumour-driving kinases in cell lines. We ﬁrst focus on the ‘drugged kinases’. Effective lentiviral shRNA vectors are currently being tested for CDK2, AURKA+B, IGF1R, ALK and PIK3CA kinases in cell line panels of each of the 6 tumours. The next series of kinases will include KIT, MET, AKT3, FYN, MEK5+6, PDGFRA, PLK1 and RAF1. Mutation and functional screening of candidate ‘tumour driving’ kinase genes will be perfomed subsequently in large series of tumour samples. High-throughput 454 direct sequencing is ongoing for a series of 13 kinases. Tissue arrays of >600 tumor samples are available to analyse protein expression and phosphorylation status of kinases. In vitro activity of novel kinase inhibitors being developed for adult oncology against the peadiatric tumour-driving kinases will be tested, including readouts of target inhibition and pathway modulation. When no inhibitor is available, a novel generation of antisense oligonucleotide inhibitor drugs (LNAs) will be developed. In vivo validation of efﬁcacy for successful compounds will be performed in established xenograft models of the six childhood tumour types. KidsCancer Kinome will contribute to a better understanding of the unique paediatric tumour biology and to the development of new drugs.