Advances in preclinical models that recapitulate chemorefractory and relapsed disease are needed to better predict the efficacy of an expanding and promising armamentarium of drug candidates being tested in early-phase pediatric clinical trials. Here, we used longitudinal magnetic resonance imaging to design an individualized, dose-escalating treatment regimen that induces evolution of neuroblastoma in the Th-MYCN genetically-engineered mouse model, concomitant with the acquisition of resistance to temozolomide, a standard chemotherapy used in treatment of refractory, relapsed neuroblastoma patients within European early-phase clinical trials. MRI longitudinally identified the development of intra-tumoral heterogeneity. Molecular profiling of expanding, treatment-refractory regions identified prominent up-regulation of the noradrenergic core regulatory signature and deregulation of the CDK2 pathway. Treatment with the CDK2/9 inhibitor fadraciclib led to significant response and an overall survival benefit in temozolomide-resistant Th-MYCN tumors and allografts generated from these resistant tumours. These findings demonstrate the utility of genetically-engineered mouse models as platforms to dissect the evolution of chemoresistance in neuroblastoma and they provide a mechanistic rationale to support the evaluation of fadraciclib in ongoing paediatric phase I studies of chemotherapy combined with temozolomide in relapsed, treatment refractory neuroblastoma patients.
Poon et al. (Wed,) studied this question.
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