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.

ITCC was created in 2003 as a European network to support the introduction of new therapies into the paediatric cancer population. There are two core arms to the network. Firstly a biology programme to evaluate new compounds in a preclinical setting with the aim of prioritising drugs for further clinical evaluation. Secondly a network of clinical centres in Europe able to deliver high quality Phase I and II clinical trials.

To date nine research laboratories are participating in the biology programme linked by a consortium agreement. These laboratories include specialist units focusing on rhabdomyodsarcoma, Ewings sarcoma and osteosacrcoma. A large biological resource of tumour samples, cell lines and gene profile data is available through this network. The clinical trials programme has identified and accredited 36 centres in six EU Member States to conduct clinical trials.

ITCC has become recognised as the major academic network for drug development in paediatric cancer in Europe. Strong collaborations have been forged with the pharmaceutical industry, and regulatory authorities to capitalise on the emerging EU legislation facilitating the development of drugs for children. We are also in a strong position to advise and partner with the major disease-specific groups developing Phase III trials in a range of tumours such that new therapies can be introduced appropriately into front-line treatment.