Noninvasive MRI Native T1 Mapping Detects Response to MYCN-targeted Therapies in the Th-MYCN Model of Neuroblastoma.
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Authors
Zormpas-Petridis, K
Poon, E
Clarke, M
Jerome, NP
Boult, JKR
Blackledge, MD
Carceller, F
Koers, A
Barone, G
Pearson, ADJ
Moreno, L
Anderson, J
Sebire, N
McHugh, K
Koh, D-M
Chesler, L
Yuan, Y
Robinson, SP
Jamin, Y
Poon, E
Clarke, M
Jerome, NP
Boult, JKR
Blackledge, MD
Carceller, F
Koers, A
Barone, G
Pearson, ADJ
Moreno, L
Anderson, J
Sebire, N
McHugh, K
Koh, D-M
Chesler, L
Yuan, Y
Robinson, SP
Jamin, Y
Document Type
Journal Article
Date
2020-08-15
Date Accepted
2020-06-11
Abstract
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. 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.
Citation
Cancer research, 2020, 80 (16), pp. 3424 - 3435
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
Research Team
Computational Pathology & Integrated Genomics
Paediatric Solid Tumour Biology and Therapeutics
Computational Imaging
Pre-Clinical MRI
Paediatric Solid Tumour Biology and Therapeutics
Computational Imaging
Pre-Clinical MRI