Noninvasive MRI Native T 1 Mapping Detects Response to MYCN -targeted Therapies in the Th- MYCN Model of Neuroblastoma.

Autor: Zormpas-Petridis K; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Poon E; Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Clarke M; Division of Molecular Pathology, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Jerome NP; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Clinic of Radiology and Nuclear Medicine, St. Olavs Hospital, Trondheim, Norway., Boult JKR; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Blackledge MD; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Carceller F; Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.; Children & Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom., Koers A; Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Barone G; Department of Pediatric Oncology, Great Ormond Street Hospital for Children, London, United Kingdom., Pearson ADJ; Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Moreno L; Pediatric Hematology & Oncology, Hospital Universitari Vall d'Hebron, Barcelona, Spain., Anderson J; Department of Pediatric Oncology, Great Ormond Street Hospital for Children, London, United Kingdom.; Institute of Child Health, University College London, London, United Kingdom., Sebire N; Institute of Child Health, University College London, London, United Kingdom.; Department of Pathology, Great Ormond Street Hospital for Children, London, United Kingdom., McHugh K; Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom., Koh DM; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Chesler L; Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Yuan Y; Division of Molecular Pathology, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Robinson SP; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom., Jamin Y; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom. Yann.Jamin@icr.ac.uk.
Jazyk: angličtina
Zdroj: Cancer research [Cancer Res] 2020 Aug 15; Vol. 80 (16), pp. 3424-3435. Date of Electronic Publication: 2020 Jun 28.
DOI: 10.1158/0008-5472.CAN-20-0133
Abstrakt: Noninvasive 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. T 1 mapping is an MRI scan that measures the proton spin-lattice relaxation time T 1 . 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 1 mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th- MYCN transgenic model. Regions with high native T 1 corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T 1 were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T 1 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 T 1 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.
(©2020 American Association for Cancer Research.)
Databáze: MEDLINE
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