Noninvasive MRI Native T<sub>1</sub> Mapping Detects Response to <i>MYCN</i>-targeted Therapies in the Th-<i>MYCN</i> Model of Neuroblastoma.
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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 <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.
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Protein Kinase Inhibitors
TOR Serine-Threonine Kinases
N-Myc Proto-Oncogene Protein
Multiparametric Magnetic Resonance Imaging
Computational Pathology & Integrated Genomics
Paediatric Solid Tumour Biology and Therapeutics
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Cancer research, 2020, 80 (16), pp. 3424 - 3435