Intrinsic susceptibility MRI identifies tumors with ALKF1174L mutation in genetically-engineered murine models of high-risk neuroblastoma.

Yann Jamin,Louis Chesler,Dow-Mu Koh,Laura Glass,Rani George,Andrew D J Pearson,Simon P Robinson,Albert Hallsworth

doi:10.1371/journal.pone.0092886

Abstract

The early identification of children presenting ALKF1174L-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALKF1174L/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALKF1174L-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R2* (s−1) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALKF1174L mutation with high specificity and selectivity. Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALKF1174L mutation at the time of diagnosis.

Highlights

Neuroblastoma arises in the sympathetic nervous system during embryogenesis and is the most common extracranial solid tumor in children [1]
The aim of our study was to demonstrate that quantitation of the transverse relaxation rate, R2*, and changes in R2* induced by breathing 100% oxygen, DR2*oxygen-air, could discriminate between tumors arising in ThALK F1174L/Th-MYCN and Th-MYCN mice, and that intrinsic susceptibility magnetic resonance imaging (MRI) could potentially provide a non-invasive and clinically-translatable method to help identify children, presenting MYCN-amplified neuroblastoma harboring the anaplastic lymphoma kinase (ALK) F1174L mutation
All the Th-ALKF1174L/Th-MYCN (n = 23) and Th-MYCN (n = 21) mice examined presented with abdominal tumors with wide range of volumes (525–3400 mm3 for tumors in Th-ALKF1174L/Th-MYCN mice and 335–2450 mm3 for tumors in Th-MYCN mice)

Summary

Introduction

Neuroblastoma arises in the sympathetic nervous system during embryogenesis and is the most common extracranial solid tumor in children [1]. The poor clinical outcome and aggressive tumor phenotype of high-risk neuroblastoma strongly correlates with amplification of the proto-oncogene MYCN and enhanced tumor angiogenesis [2]. The most common and potent ALK mutation, ALKF1174L, is associated preferentially with MYCN amplification, a markedly poorer prognosis, and confers resistance to the promising ALK inhibitor crizotinib [3,4,5]. With crizotinib in pediatric phase I clinical trials, and other ALK inhibitor studies in development, a current challenge is to rapidly identify upfront children with high-risk ALK mutated or amplified neuroblastoma who may benefit from or become resistant to ALK-

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