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dc.contributor.authorCarvalho, D
dc.contributor.authorTaylor, KR
dc.contributor.authorOlaciregui, NG
dc.contributor.authorMolinari, V
dc.contributor.authorClarke, M
dc.contributor.authorMackay, A
dc.contributor.authorRuddle, R
dc.contributor.authorHenley, A
dc.contributor.authorValenti, M
dc.contributor.authorHayes, A
dc.contributor.authorBrandon, ADH
dc.contributor.authorEccles, SA
dc.contributor.authorRaynaud, F
dc.contributor.authorBoudhar, A
dc.contributor.authorMonje, M
dc.contributor.authorPopov, S
dc.contributor.authorMoore, AS
dc.contributor.authorMora, J
dc.contributor.authorCruz, O
dc.contributor.authorVinci, M
dc.contributor.authorBrennan, PE
dc.contributor.authorBullock, AN
dc.contributor.authorCarcaboso, AM
dc.contributor.authorJones, C
dc.date.accessioned2019-05-14T13:12:32Z
dc.date.issued2019-01
dc.identifier.citationCommunications biology, 2019, 2 pp. 156 - ?
dc.identifier.issn2399-3642
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3227
dc.identifier.eissn2399-3642
dc.identifier.doi10.1038/s42003-019-0420-8
dc.description.abstractDiffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in <i>ACVR1</i>, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of <i>ACVR1</i> 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, <i>ACVR1</i>R206H 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.
dc.formatElectronic-eCollection
dc.format.extent156 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectBrain Stem Neoplasms
dc.subjectPyrazoles
dc.subjectPyridines
dc.subjectPyrimidines
dc.subjectActivin Receptors, Type I
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectAdministration, Oral
dc.subjectDrug Administration Schedule
dc.subjectSurvival Analysis
dc.subjectDrug Evaluation, Preclinical
dc.subjectXenograft Model Antitumor Assays
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectGene Expression
dc.subjectMutation
dc.subjectChild
dc.subjectFemale
dc.subjectHigh-Throughput Screening Assays
dc.subjectDiffuse Intrinsic Pontine Glioma
dc.titleALK2 inhibitors display beneficial effects in preclinical models of <i>ACVR1</i> mutant diffuse intrinsic pontine glioma.
dc.typeJournal Article
dcterms.dateAccepted2019-04-08
rioxxterms.versionofrecord10.1038/s42003-019-0420-8
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCommunications biology
pubs.notesNo embargo
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.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
pubs.volume2en_US
pubs.embargo.termsNo embargo
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorJones, Chrisen
dc.contributor.icrauthorMackay, Alanen


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