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

doi:10.1158/1078-0432.CCR-15-0313

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

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

47 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-2	Engels
Pagina's (van-tot)	5100-5109
Aantal pagina's	10
Tijdschrift	Clinical Cancer Research
Volume	21
Nummer van het tijdschrift	22
DOI's	https://doi.org/10.1158/1078-0432.CCR-15-0313
Status	Gepubliceerd - 15 nov. 2015
Extern gepubliceerd	Ja

Toegang tot document

10.1158/1078-0432.CCR-15-0313

Citeer dit

Dolman, M. E. M., Poon, E., Ebus, M. E., Den Hartog, I. J. M., Van Noesel, C. J. M., Jamin, Y., Hallsworth, A., Robinson, S. P., Petrie, K., Sparidans, R. W., Kok, R. J., Versteeg, R., Caron, H. N., Chesler, L., & Molenaar, J. J. (2015). Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. Clinical Cancer Research, 21(22), 5100-5109. https://doi.org/10.1158/1078-0432.CCR-15-0313

@article{c6db2718146e4d84aa0b2cf2eea8df47,

title = "Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma",

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.",

keywords = "Animals, Apoptosis/drug effects, Cell Line, Tumor, Cell Proliferation/drug effects, Cyclin-Dependent Kinase 2/biosynthesis, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, N-Myc Proto-Oncogene Protein, Neuroblastoma/drug therapy, Nuclear Proteins/biosynthesis, Oncogene Proteins/biosynthesis, Piperidines/administration & dosage, Protein Kinase Inhibitors/administration & dosage, Pyrazoles/administration & dosage, Xenograft Model Antitumor Assays",

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

note = "Publisher Copyright: {\textcopyright} 2015 American Association for Cancer Research.",

year = "2015",

month = nov,

day = "15",

doi = "10.1158/1078-0432.CCR-15-0313",

language = "English",

volume = "21",

pages = "5100--5109",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "22",

}

Dolman, MEM, Poon, E, Ebus, ME, Den Hartog, IJM, Van Noesel, CJM, Jamin, Y, Hallsworth, A, Robinson, SP, Petrie, K, Sparidans, RW, Kok, RJ, Versteeg, R, Caron, HN, Chesler, L & Molenaar, JJ 2015, 'Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma', Clinical Cancer Research, vol. 21, nr. 22, blz. 5100-5109. https://doi.org/10.1158/1078-0432.CCR-15-0313

TY - JOUR

T1 - Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma

AU - Dolman, M. Emmy M.

AU - Poon, Evon

AU - Ebus, Marli E.

AU - Den Hartog, Ilona J.M.

AU - Van Noesel, Carel J.M.

AU - Jamin, Yann

AU - Hallsworth, Albert

AU - Robinson, Simon P.

AU - Petrie, Kevin

AU - Sparidans, Rolf W.

AU - Kok, Robbert J.

AU - Versteeg, Rogier

AU - Caron, Huib N.

AU - Chesler, Louis

AU - Molenaar, Jan J.

PY - 2015/11/15

Y1 - 2015/11/15

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis/drug effects

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Cyclin-Dependent Kinase 2/biosynthesis

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Mice

KW - N-Myc Proto-Oncogene Protein

KW - Neuroblastoma/drug therapy

KW - Nuclear Proteins/biosynthesis

KW - Oncogene Proteins/biosynthesis

KW - Piperidines/administration & dosage

KW - Protein Kinase Inhibitors/administration & dosage

KW - Pyrazoles/administration & dosage

KW - Xenograft Model Antitumor Assays

UR - http://www.scopus.com/inward/record.url?scp=84943642374&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-0313

DO - 10.1158/1078-0432.CCR-15-0313

M3 - Article

C2 - 26202950

AN - SCOPUS:84943642374

SN - 1078-0432

VL - 21

SP - 5100

EP - 5109

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 22

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit