Abstract
In this lecture I will present an update on the activities of the European KCK (KidsCancerKinome) consortium. Nine European research centers devoted to molecular-biologic, pharmacologic and clinical studies of childhood cancers and two SMEs are engaged in the KidsCancerKinome consortium. The research centers already have an established collaboration for pre-clinical evaluation of anti-cancer compounds in the European ‘Innovative Therapies for Children with Cancer’ consortium (ITCC).
The KidsCancerKinome consortium aims to perform a comprehensive analysis of the human protein kinase family in childhood tumors, as protein kinases are excellent targets for small inhibitory molecules designed for adult tumors, and many more of such drugs are currently in development. Six aggressive childhood tumors, killing ~2000 children in Europe annually, will be addressed, i.e Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL.
The KCK consortium has generated gene expression profiles (Affy U133plus2 arrays) of > 500 tumor samples form those six tumortypes. We have performed extensive analyses of mRNa expression of human kinases. Examples of interesting expression patterns of the human kinome will be presented. Detailed analyses for the first 5 kinases for which targetted 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 lines to validate those kinases as drug targets.
Many novel kinase inhibitors are under development for adult oncology and KCK will test their in vitro activity against the tumor-driving kinases identified in this program. We are currently testing small molecule inhibitors for the first 5 kinases. For those kinases that have no small molecule inhibitors, a novel generation of siRNA based nucleic acid drugs (LNAs), produced by the Santaris company, will be applied and tested in vitro. Successful small molecule inhibitors and LNAs will be taken further to in vivo validation in established xenograft models of the six childhood tumor types. Pharmaco-kinetic studies of these drugs will finally prepare them.
Correspondence should be addressed to Professor Stefan Bielack, Olgahospital, Klinikum Stuttgart, Bismarkstrasse 8, D-70176 Stuttgart, Germany. Email: s.bielack@klinikum_stuttgart.de
