journal contribution
posted on 2023-03-31, 03:45 authored by Konstantinos Zormpas-Petridis, Evon Poon, Matthew Clarke, Neil P. Jerome, Jessica K.R. Boult, Matthew D. Blackledge, Fernando Carceller, Alexander Koers, Giuseppe Barone, Andrew D.J. Pearson, Lucas Moreno, John Anderson, Neil Sebire, Kieran McHugh, Dow-Mu Koh, Louis Chesler, Yinyin Yuan, Simon P. Robinson, Yann Jamin Table S1: MRI acquisition parameters, Supplementary results including Table S2 summarising the subregional analysis, Table S3: confusion matrix for cell classification, Figure S1 showing tumor volumes at the time of enrolment, Figure S2 showing individual therapy-induced changes in volume, Figure S3 showing the validation of our algorithm for the automatic classification of apoptotic cells from HE-stained slides digitised images with cleaved caspase-3 imunohistochemistry, Figure S4 showing cleaved caspase-3 imunohistochemistry.
Funding
Children with Cancer UK Research
Rosetrees Trust
Cancer Research UK
Children with Cancer UK Project
George and Giant Pledge via the Royal Marsden Cancer Charity
GOSHCC
EPSRC
NIHR GOSH Biomedical Research Centre
Oak Foundation
History
ARTICLE 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.
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.
