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dc.contributor.authorPearson, AD
dc.contributor.authorDuBois, SG
dc.contributor.authorBuenger, V
dc.contributor.authorKieran, M
dc.contributor.authorStegmaier, K
dc.contributor.authorBandopadhayay, P
dc.contributor.authorBennett, K
dc.contributor.authorBourdeaut, F
dc.contributor.authorBrown, PA
dc.contributor.authorChesler, L
dc.contributor.authorClymer, J
dc.contributor.authorFox, E
dc.contributor.authorFrench, CA
dc.contributor.authorGermovsek, E
dc.contributor.authorGiles, FJ
dc.contributor.authorBender, JG
dc.contributor.authorHattersley, MM
dc.contributor.authorLudwinski, D
dc.contributor.authorLuptakova, K
dc.contributor.authorMaris, J
dc.contributor.authorMcDonough, J
dc.contributor.authorNikolova, Z
dc.contributor.authorSmith, M
dc.contributor.authorTsiatis, AC
dc.contributor.authorVibhakar, R
dc.contributor.authorWeiner, S
dc.contributor.authorYi, JS
dc.contributor.authorZheng, F
dc.contributor.authorVassal, G
dc.coverage.spatialEngland
dc.date.accessioned2022-09-15T13:12:50Z
dc.date.available2022-09-15T13:12:50Z
dc.date.issued2021-02-16
dc.identifierS0959-8049(21)00030-7
dc.identifier.citationEuropean Journal of Cancer, 2021, 146 pp. 115 - 124en_US
dc.identifier.issn0959-8049
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5487
dc.identifier.eissn1879-0852
dc.identifier.eissn1879-0852
dc.identifier.doi10.1016/j.ejca.2021.01.018
dc.description.abstractBased on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.
dc.formatPrint-Electronic
dc.format.extent115 - 124
dc.languageeng
dc.language.isoengen_US
dc.publisherELSEVIER SCI LTDen_US
dc.relation.ispartofEuropean Journal of Cancer
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectBET inhibitors
dc.subjectBromodomain
dc.subjectCancer therapeutics
dc.subjectDrug development
dc.subjectEpigenetic mechanisms
dc.subjectMYC/MYCN
dc.subjectNUT
dc.subjectPaediatric Strategy Forum
dc.subjectPaediatric oncology
dc.subjectAntineoplastic Agents
dc.subjectChild
dc.subjectConsensus
dc.subjectDrug Development
dc.subjectEpigenesis, Genetic
dc.subjectHumans
dc.subjectMolecular Targeted Therapy
dc.subjectNeoplasms
dc.subjectProteins
dc.titleBromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.en_US
dc.typeJournal Article
dcterms.dateAccepted2021-01-05
dc.date.updated2022-09-15T13:12:24Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1016/j.ejca.2021.01.018en_US
rioxxterms.licenseref.startdate2021-02-16
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/33601323
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.publication-statusPublished
pubs.publisher-urlhttp://dx.doi.org/10.1016/j.ejca.2021.01.018
pubs.volume146
icr.researchteamPaediatric Tumour Biologyen_US
dc.contributor.icrauthorChesler, Louis
icr.provenanceDeposited by Mr Arek Surman on 2022-09-15. Deposit type is initial. No. of files: 1. Files: 1-s2.0-S0959804921000307-main.pdf


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