The KidsCancerKinome – Validation of Drug Targets for High Risk Childhood Cancers
The aim of KCK is the pre-clinical selection and validation of drug targets and corresponding targeted drugs for 6 high-risk childhood cancers. The KCK consortium focuses on six aggressive childhood tumors, killing ˜2000 children in Europe annually, i.e Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL. The KidsCancerKinome (KCK) project is funded by the EU in the FP6 programme and consists of 9 tumor biology labs in 4 European countries.
The experimental approach encompasses:
target presence analyses (mRNA and protein expression of the human kinome)
molecular validation of kinase tumor dependency (RNAi)
kinase mutation analysis
in vitro drug efficacy testing
in vivo proof-of-principle of drug efficacy
The KCK consortium has generated gene expression profiles (Affy U133plus2 arrays) of >500 clinical tumor samples from those six tumor types. We have performed extensive analyses of mRNA expression of human kinases. Tissue microarrays with >800 tumor samples have been analysed for various kinases and for phosphorylation status of downstream proteins. Examples of interesting expression patterns of the human kinome will be presented. Detailed analyses for the first 5 kinases for which targeted drugs are available, i.e. PI3K, IGF1R, AURKA+B, and CDK2, will be presented. Lentiviral shRNA-mediated knockdown of kinase protein expression has been used in cell line panels for each tumor type to select kinases with tumor dependency as validated drug targets.