title: Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.
abstract: OBJECTIVE
  MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519.
  
  
  METHODS
  Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma.
  
  
  RESULTS
  AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug.
  
  
  CONCLUSIONS
  This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification.
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. memdolman@gmail.com.
authors.forename: M Emmy M
authors.initials: ME
authors.lastname: Dolman
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, England.
authors.forename: Evon
authors.initials: E
authors.lastname: Poon
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marli E
authors.initials: ME
authors.lastname: Ebus
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ilona J M
authors.initials: IJ
authors.lastname: den Hartog
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, England.
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, England.
authors.forename: Albert
authors.initials: A
authors.lastname: Hallsworth
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, England.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, England.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.affiliation: Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, London, England.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D010880:Piperidines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C531230:4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2