Noninvasive MRI Native T1 Mapping Detects Response to MYCN-targeted Therapies in the Th-MYCN Model of Neuroblastoma

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.