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dc.contributor.authorZormpas-Petridis, Ken_US
dc.contributor.authorPoon, Een_US
dc.contributor.authorClarke, Men_US
dc.contributor.authorJerome, NPen_US
dc.contributor.authorBoult, JKRen_US
dc.contributor.authorBlackledge, MDen_US
dc.contributor.authorCarceller, Fen_US
dc.contributor.authorKoers, Aen_US
dc.contributor.authorBarone, Gen_US
dc.contributor.authorPearson, ADJen_US
dc.contributor.authorMoreno, Len_US
dc.contributor.authorAnderson, Jen_US
dc.contributor.authorSebire, Nen_US
dc.contributor.authorMcHugh, Ken_US
dc.contributor.authorKoh, D-Men_US
dc.contributor.authorChesler, Len_US
dc.contributor.authorYuan, Yen_US
dc.contributor.authorRobinson, SPen_US
dc.contributor.authorJamin, Yen_US
dc.date.accessioned2020-06-15T08:37:44Z
dc.date.issued2020-08en_US
dc.identifier.citationCancer research, 2020, 80 (16), pp. 3424 - 3435en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3731
dc.identifier.eissn1538-7445en_US
dc.identifier.doi10.1158/0008-5472.can-20-0133en_US
dc.description.abstractNoninvasive early indicators of treatment response are crucial to the successful delivery of precision medicine in children with cancer. Neuroblastoma is a common solid tumor of young children that arises from anomalies in neural crest development. Therapeutic approaches aiming to destabilize <i>MYCN</i> protein, such as small-molecule inhibitors of Aurora A and mTOR, are currently being evaluated in early phase clinical trials in children with high-risk <i>MYCN</i>-driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T<sub>1</sub> mapping is an MRI scan that measures the proton spin-lattice relaxation time T<sub>1</sub>. Using a multiparametric MRI-pathologic cross-correlative approach and computational pathology methodologies including a machine learning-based algorithm for the automatic detection and classification of neuroblasts, we show here that T<sub>1</sub> mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th-<i>MYCN</i> transgenic model. Regions with high native T<sub>1</sub> corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T<sub>1</sub> were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T<sub>1</sub> represented a sensitive biomarker of response to treatment-induced apoptosis with two <i>MYCN</i>-targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T<sub>1</sub> mapping, a scan readily available on most clinical MRI scanners, to assess response to therapy and guide clinical trials for children with neuroblastoma. The study reinforces the potential role of MRI-based functional imaging in delivering precision medicine to children with neuroblastoma. SIGNIFICANCE: This study shows that MRI-based functional imaging can detect apoptotic responses to <i>MYCN</i>-targeted small-molecule inhibitors in a genetically engineered murine model of <i>MYCN</i>-driven neuroblastoma.en_US
dc.formatPrint-Electronicen_US
dc.format.extent3424 - 3435en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAnimalsen_US
dc.subjectMice, Transgenicen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectNeuroblastomaen_US
dc.subjectBenzamidesen_US
dc.subjectAzepinesen_US
dc.subjectMorpholinesen_US
dc.subjectPyrimidinesen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectTreatment Outcomeen_US
dc.subjectAlgorithmsen_US
dc.subjectTime Factorsen_US
dc.subjectChilden_US
dc.subjectFemaleen_US
dc.subjectMaleen_US
dc.subjectTOR Serine-Threonine Kinasesen_US
dc.subjectMachine Learningen_US
dc.subjectPrecision Medicineen_US
dc.subjectN-Myc Proto-Oncogene Proteinen_US
dc.subjectMultiparametric Magnetic Resonance Imagingen_US
dc.titleNoninvasive MRI Native T<sub>1</sub> Mapping Detects Response to <i>MYCN</i>-targeted Therapies in the Th-<i>MYCN</i> Model of Neuroblastoma.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-06-11en_US
rioxxterms.versionofrecord10.1158/0008-5472.can-20-0133en_US
rioxxterms.licenseref.startdate2020-08en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCancer researchen_US
pubs.issue16en_US
pubs.notesNot knownen_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/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/Computational Pathology & Integrated Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Computational Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume80en_US
pubs.embargo.termsNot knownen_US
icr.researchteamComputational Pathology & Integrated Genomicsen_US
icr.researchteamPaediatric Solid Tumour Biology and Therapeuticsen_US
icr.researchteamComputational Imagingen_US
icr.researchteamPre-Clinical MRIen_US
dc.contributor.icrauthorKoh, Dow-Muen_US
dc.contributor.icrauthorJamin, Yannen_US
dc.contributor.icrauthorZormpas Petridis, Konstantinosen_US
dc.contributor.icrauthorPoon, Evonen_US
dc.contributor.icrauthorRobinson, Simonen_US
dc.contributor.icrauthorBoult, Jessicaen_US
dc.contributor.icrauthorChesler, Louisen_US
dc.contributor.icrauthorYuan, Yinyinen_US
dc.contributor.icrauthorBlackledge, Matthewen_US


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