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 vital for the effective delivery of precision medicine in pediatric cancer patients. Neuroblastoma, a common solid tumor in young children, originates from abnormalities in neural crest development. Current therapeutic strategies, including small-molecule inhibitors targeting MYCN protein destabilization—such as Aurora A and mTOR inhibitors—are being assessed in early phase clinical trials for children with high-risk, MYCN-driven neuroblastoma. However, these trials face challenges in evaluating conventional pharmacodynamic biomarkers of treatment response.

T1 mapping, an MRI technique that measures proton spin-lattice relaxation time, has emerged as a promising tool. By employing a multiparametric MRI-pathologic cross-correlation and computational pathology methods, including a machine learning algorithm for the automatic detection and classification of neuroblasts, we demonstrate that T1 mapping effectively captures the complex histopathologic diversity of neuroblastoma in the Th-MYCN transgenic model. Areas with high native T1 were associated with regions dense in proliferative, undifferentiated neuroblasts, whereas areas with low T1 were rich in apoptotic or differentiating neuroblasts. A decrease in tumor-native T1 served as a sensitive biomarker of response to apoptosis induced by two MYCN-targeted small-molecule inhibitors: the Aurora A kinase inhibitor alisertib (MLN8237) and the mTOR inhibitor vistusertib (AZD2014).

This study underscores the potential of T1 mapping, an MRI scan widely available on most clinical MRI machines, to monitor treatment response and guide clinical trials for children with neuroblastoma. It highlights the promising role of MRI-based functional imaging in advancing precision medicine for pediatric neuroblastoma patients.

**SIGNIFICANCE:** This research demonstrates that MRI-based functional imaging can detect apoptotic responses to MYCN-targeted small-molecule inhibitors in a genetically engineered mouse model of MYCN-driven neuroblastoma.