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dc.contributor.authorMorfouace, Marie
dc.contributor.authorNimmervoll, Birgit
dc.contributor.authorBoulos, Nidal
dc.contributor.authorPatel, Yogesh T
dc.contributor.authorShelat, Anang
dc.contributor.authorFreeman, Burgess B
dc.contributor.authorRobinson, Giles W
dc.contributor.authorWright, Karen
dc.contributor.authorGajjar, Amar
dc.contributor.authorStewart, Clinton F
dc.contributor.authorGilbertson, Richard J
dc.contributor.authorRoussel, Martine F
dc.date.accessioned2018-11-14T00:30:22Z
dc.date.available2018-11-14T00:30:22Z
dc.date.issued2016-01
dc.identifier.issn0167-594X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285016
dc.description.abstractChemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBrain
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice
dc.subjectMice, Nude
dc.subjectBrain Neoplasms
dc.subjectDisease Models, Animal
dc.subjectDeoxycytidine
dc.subjectTetrahydrouridine
dc.subjectAntineoplastic Agents
dc.subjectDrug Evaluation, Preclinical
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectEpigenesis, Genetic
dc.subjectDose-Response Relationship, Drug
dc.titlePreclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.
dc.typeArticle
prism.endingPage234
prism.issueIdentifier2
prism.publicationDate2016
prism.publicationNameJ Neurooncol
prism.startingPage225
prism.volume126
dc.identifier.doi10.17863/CAM.32386
dcterms.dateAccepted2015-10-19
rioxxterms.versionofrecord10.1007/s11060-015-1965-0
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-01
dc.contributor.orcidNimmervoll, Birgit [0000-0002-3324-092X]
dc.contributor.orcidGilbertson, Richard [0000-0001-7539-9472]
dc.identifier.eissn1573-7373
rioxxterms.typeJournal Article/Review
pubs.funder-project-idNational Cancer Institute (R01CA129541)
pubs.funder-project-idNational Cancer Institute (P01CA096832)
cam.issuedOnline2015-10-30


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International