Show simple item record

dc.contributor.authorCarvalho, Den_US
dc.contributor.authorTaylor, KRen_US
dc.contributor.authorOlaciregui, NGen_US
dc.contributor.authorMolinari, Ven_US
dc.contributor.authorClarke, Men_US
dc.contributor.authorMackay, Aen_US
dc.contributor.authorRuddle, Ren_US
dc.contributor.authorHenley, Aen_US
dc.contributor.authorValenti, Men_US
dc.contributor.authorHayes, Aen_US
dc.contributor.authorBrandon, ADHen_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorRaynaud, Fen_US
dc.contributor.authorBoudhar, Aen_US
dc.contributor.authorMonje, Men_US
dc.contributor.authorPopov, Sen_US
dc.contributor.authorMoore, ASen_US
dc.contributor.authorMora, Jen_US
dc.contributor.authorCruz, Oen_US
dc.contributor.authorVinci, Men_US
dc.contributor.authorBrennan, PEen_US
dc.contributor.authorBullock, ANen_US
dc.contributor.authorCarcaboso, AMen_US
dc.contributor.authorJones, Cen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2019-05-14T13:12:32Z
dc.date.issued2019en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/31098401en_US
dc.identifier420en_US
dc.identifier.citationCommun Biol, 2019, 2 pp. 156 - ?en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3227
dc.identifier.eissn2399-3642en_US
dc.identifier.doi10.1038/s42003-019-0420-8en_US
dc.description.abstractDiffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.en_US
dc.format.extent156 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCNS canceren_US
dc.subjectPaediatric canceren_US
dc.subjectTarget validationen_US
dc.titleALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-04-08en_US
rioxxterms.versionofrecord10.1038/s42003-019-0420-8en_US
rioxxterms.licenseref.startdate2019en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCommun Biolen_US
pubs.notesNo embargoen_US
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/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team
pubs.publication-statusPublished onlineen_US
pubs.volume2en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorJones, Chrisen_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorMackay, Alanen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

http://creativecommons.org/licenses/by/4.0/
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/