dc.contributor.author | Dolman, MEM | |
dc.contributor.author | Poon, E | |
dc.contributor.author | Ebus, ME | |
dc.contributor.author | den Hartog, IJM | |
dc.contributor.author | van Noesel, CJM | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Hallsworth, A | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Petrie, K | |
dc.contributor.author | Sparidans, RW | |
dc.contributor.author | Kok, RJ | |
dc.contributor.author | Versteeg, R | |
dc.contributor.author | Caron, HN | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Molenaar, JJ | |
dc.date.accessioned | 2019-04-02T13:43:25Z | |
dc.date.issued | 2015-11-15 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2015, 21 (22), pp. 5100 - 5109 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3167 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-15-0313 | |
dc.description.abstract | PURPOSE: 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. EXPERIMENTAL DESIGN: 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 5100 - 5109 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neuroblastoma | |
dc.subject | Piperidines | |
dc.subject | Pyrazoles | |
dc.subject | Oncogene Proteins | |
dc.subject | Nuclear Proteins | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Apoptosis | |
dc.subject | Cell Proliferation | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Female | |
dc.subject | Cyclin-Dependent Kinase 2 | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.title | Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-07-09 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-15-0313 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2015-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 22 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.publication-status | Published | |
pubs.volume | 21 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
dc.contributor.icrauthor | Poon, Evon | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Petrie, Kevin | |
dc.contributor.icrauthor | Chesler, Louis | |