Abstract 5037: Intrinsic susceptibility magnetic resonance imaging identifies tumors with ALKF1174L mutation in transgenic murine models of high-risk neuroblastoma.
Authors: Jamin Yann , Glass Laura , Hallsworth Albert , George Rani E. , Koh Dow-Mu , Pearson Andrew D.J. , Chesler Louis , Robinson Simon P. 
Published: August 2014

In neuroblastoma, mutations in the anaplastic lymphoma kinase (ALK) tyrosine kinase gene have been identified in 8-10 % of primary tumors. The most common and potent ALK mutation, ALKF1174L, leads to the constitutive activation of the ALK protein and is associated preferentially with MYCN amplification, a markedly poorer prognosis, and confers resistance to the promising ALK inhibitor crizotinib. The development of more efficacious ALK inhibitors will benefit from non-invasive imaging strategies for the rapid identification of children with high-risk ALK-expressing or mutated neuroblastoma.

Intrinsic susceptibility magnetic resonance imaging (IS-MRI) data was acquired from tumors arising in TH-ALKF1174L/TH-MYCN and TH-MYCN mice, two genetically engineered mouse model of high-risk neuroblastoma. The native MRI transverse relaxation rate R2*, an imaging biomarker sensitive to the concentration of paramagnetic deoxyhemoglobin, and changes in R2* induced with 100% oxygen inhalation, were quantified. Tumors in the TH-ALKF1174L/TH-MYCN mice demonstrated significantly (p&lt;0.0001) slower native R2* rates (61 ± 3s−1, n=23) than tumors in the TH-MYCN mice (101 ± 6s−1, n=21). With hyperoxic challenge, the TH-ALKF1174L/TH-MYCN mice demonstrated a significantly (p&lt;0.0001) lower and negligible ΔR2*oxygen-air (-3 ± 1s−1, n=10) compared with tumors in TH-MYCN mice (-26 ± 3s−1, n=12). A sensitivity of 90% and a specificity of 81% for native R2*, and a sensitivity of 90% and a specificity of 94% for hyperoxia-induced ΔR2* was determined.

Histological correlates revealed a significantly (p&lt;0.05) higher uptake of the perfusion marker Hoechst 33342, and the presence of large hemorrhagic blood lakes filled with stagnant deoxygenated erythrocytes, in tumors within the TH-MYCN mice, but not the TH-ALKF1174L/TH-MYCN model. Together these corroborate the IS-MRI findings (relatively fast native R2* and significant ΔR2*, indicative of vascular instability, in tumors in the TH-MYCN mice).

IS-MRI provides a robust method to discriminate and identify TH-MYCN transgenic mice harboring the ALKF1174L mutation based on a stark differential vascular phenotype, which may impact on impaired drug delivery. IS-MRI is suitable for the scanning of young children, and quantitation of native R2* easily incorporated into existing pediatric clinical imaging protocols. This approach could provide a robust and rapid indicator of ALK genotypic status of the tumor, enabling the early identification of children with ultra high-risk neuroblastoma at the time of diagnosis.

Citation Format: Yann Jamin, Laura Glass, Albert Hallsworth, Rani E. George, Dow-Mu Koh, Andrew D.J. Pearson, Louis Chesler, Simon P. Robinson. Intrinsic susceptibility magnetic resonance imaging identifies tumors with ALKF1174L mutation in transgenic murine models of high-risk neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2013-5037