Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma

M. Emmy M. Dolman, Evon Poon, Marli E. Ebus, Ilona J.M. Den Hartog, Carel J.M. Van Noesel, Yann Jamin, Albert Hallsworth, Simon P. Robinson, Kevin Petrie, Rolf W. Sparidans, Robbert J. Kok, Rogier Versteeg, Huib N. Caron, Louis Chesler, Jan J. Molenaar

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41 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)5100-5109
Aantal pagina's10
TijdschriftClinical Cancer Research
Volume21
Nummer van het tijdschrift22
DOI's
StatusGepubliceerd - 15 nov. 2015
Extern gepubliceerdJa

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