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dc.contributor.authorZormpas-Petridis, K
dc.contributor.authorPoon, E
dc.contributor.authorClarke, M
dc.contributor.authorJerome, NP
dc.contributor.authorBoult, JKR
dc.contributor.authorBlackledge, MD
dc.contributor.authorCarceller, F
dc.contributor.authorKoers, A
dc.contributor.authorBarone, G
dc.contributor.authorPearson, ADJ
dc.contributor.authorMoreno, L
dc.contributor.authorAnderson, J
dc.contributor.authorSebire, N
dc.contributor.authorMcHugh, K
dc.contributor.authorKoh, D-M
dc.contributor.authorChesler, L
dc.contributor.authorYuan, Y
dc.contributor.authorRobinson, SP
dc.contributor.authorJamin, Y
dc.date.accessioned2020-06-15T08:37:44Z
dc.date.issued2020-08-15
dc.identifier.citationCancer research, 2020, 80 (16), pp. 3424 - 3435
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3731
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-20-0133
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 MYCN 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 MYCN-driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T1 mapping is an MRI scan that measures the proton spin-lattice relaxation time T1. 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 T1 mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th-MYCN transgenic model. Regions with high native T1 corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T1 were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T1 represented a sensitive biomarker of response to treatment-induced apoptosis with two MYCN-targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T1 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 MYCN-targeted small-molecule inhibitors in a genetically engineered murine model of MYCN-driven neuroblastoma.
dc.formatPrint-Electronic
dc.format.extent3424 - 3435
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectHumans
dc.subjectMice
dc.subjectNeuroblastoma
dc.subjectBenzamides
dc.subjectAzepines
dc.subjectMorpholines
dc.subjectPyrimidines
dc.subjectProtein Kinase Inhibitors
dc.subjectTreatment Outcome
dc.subjectAlgorithms
dc.subjectTime Factors
dc.subjectChild
dc.subjectFemale
dc.subjectMale
dc.subjectTOR Serine-Threonine Kinases
dc.subjectMachine Learning
dc.subjectPrecision Medicine
dc.subjectN-Myc Proto-Oncogene Protein
dc.subjectMultiparametric Magnetic Resonance Imaging
dc.titleNoninvasive MRI Native T1 Mapping Detects Response to MYCN-targeted Therapies in the Th-MYCN Model of Neuroblastoma.
dc.typeJournal Article
dcterms.dateAccepted2020-06-11
rioxxterms.versionofrecord10.1158/0008-5472.can-20-0133
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue16
pubs.notesNot known
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.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-statusPublished
pubs.volume80
pubs.embargo.termsNot known
icr.researchteamComputational Pathology & Integrated Genomics
icr.researchteamPaediatric Solid Tumour Biology and Therapeutics
icr.researchteamComputational Imaging
icr.researchteamPre-Clinical MRI
dc.contributor.icrauthorZormpas Petridis, Konstantinos
dc.contributor.icrauthorPoon, Evon
dc.contributor.icrauthorClarke, Matthew
dc.contributor.icrauthorBoult, Jessica
dc.contributor.icrauthorBlackledge, Matthew
dc.contributor.icrauthorChesler, Louis
dc.contributor.icrauthorYuan, Yinyin
dc.contributor.icrauthorRobinson, Simon
dc.contributor.icrauthorJamin, Yann


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