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Caron, Huib N.; Westerhout, Ellen M.; Molenaar, Jan J.; Boer den, Monique L.; Clifford, Steve C.; Delattre, Olivier; Geoerger, Birgit; Lanvers, Claudia; Pietsch, Torsten; Scotlandi, Katia; Sera, Massimo; Shipley, Janet; Vassal, Gilles; Versteeg, Rogier; Verschuur, Arnauld

Abstract C116: The KidsCancerKinome: Validation of drug targets for high risk childhood cancers

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  • Medientyp: E-Artikel
  • Titel: Abstract C116: The KidsCancerKinome: Validation of drug targets for high risk childhood cancers
  • Beteiligte: Caron, Huib N.; Westerhout, Ellen M.; Molenaar, Jan J.; Boer den, Monique L.; Clifford, Steve C.; Delattre, Olivier; Geoerger, Birgit; Lanvers, Claudia; Pietsch, Torsten; Scotlandi, Katia; Sera, Massimo; Shipley, Janet; Vassal, Gilles; Versteeg, Rogier; Verschuur, Arnauld
  • Erschienen: American Association for Cancer Research (AACR), 2009
  • Erschienen in: Molecular Cancer Therapeutics
  • Sprache: Englisch
  • DOI: 10.1158/1535-7163.targ-09-c116
  • ISSN: 1538-8514; 1535-7163
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>The experimental approach encompasses the following points:target presence analyses (mRNA and protein expression of the human kinome)molecular validation of kinase tumor dependency (RNAi)kinase mutation analysisin vitro drug efficacy testingin vivo proof-of-principle of drug efficacy</jats:p> <jats:p>The KCK consortium has generated gene expression profiles (Affy U133plus2 arrays) of &amp;gt;500 clinical tumor samples form those six tumor types. We have performed extensive analyses of mRNA expression of human kinases. Tissue microarrays with &amp;gt;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.</jats:p> <jats:p>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 in in vivo validation in established xenograft models of the six childhood tumor types. Pharmacokinetic studies of these drugs will finally prepare them for evaluation in future clinical studies in childhood cancer patients.</jats:p> <jats:p>Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C116.</jats:p>
  • Zugangsstatus: Freier Zugang