Characterization of Neuroblastoma Tumor Behavior by Molecular Imaging
Date Issued
2016
Date
2016
Author(s)
Liu, Yen-Lin
Abstract
Neuroblastoma (NB) is a devastating tumor that usually occurs in young children. More than 50% of patients are diagnosed with metastatic diseases or other high-risk features, who suffer from a dismal prognosis. Therefore, a multitude of imaging studies are required for the staging and surveillance of NB. This study aims to characterize NB tumor behavior using molecular imaging modalities. First, we showed that positron emission tomography (PET) with 18F-fluoro-dihydroxyphenylalanine (FDOPA), a radiolabeled amino acid targeting catecholamine metabolism, had a sensitivity of 97.6% (87.4%–99.9%) and a specificity of 87.5% (47.3%–99.7%) and may compliment current 123I-metaiodobenzylguanidine (123I-MIBG) and 18F-fluorodeoxyglucose (FDG) PET scans. Next, NB patients undergoing paired FDG and FDOPA PET scans at diagnosis during 2007–2014 (N = 42; median age, 2.0 years; 28 boys and 14 girls;) were evaluated for the maximum standardized uptake value (SUVmax) of FDG or FDOPA by the primary tumor, revealing that NB with older age, advanced stages, or MYCN amplification showed higher FDG and lower FDOPA SUVmax (all P < 0.02). Receiver operating characteristics analysis identified FDG SUVmax ≥ 3.31 and FDOPA SUVmax < 4.12 as an ultra-high-risk feature (PET-UHR) that distinguished the most unfavorable genomic types, i.e. segmental chromosomal alterations and/or MYCN amplification, at a sensitivity of 81.3% (54.4%–96.0%) and a specificity of 93.3% (68.1%–99.8%). Considering with age, stage, MYCN status, and anatomical image-defined risk factor, PET-UHR was an independent predictor of inferior event-free survival (multivariate hazard ratio, 4.9 [1.9–30.1]; P = 0.012) and was associated lower likelihood of gross total resection of the main tumor (46% vs. 100%; P = 0.04). Meanwhile, the ratio between FDG and FDOPA SUVmax (G:D) correlated positively with hexokinase 2 (HK2; Spearman’s ρ = 0.86, P < 0.0001) and negatively with DOPA decarboxylase (DDC; ρ = -0.58, P = 0.02) gene expression levels, suggesting higher glycolytic activity and less catecholaminergic differentiation in NB tumors taking up higher FDG and lower FDOPA. Finally, we incorporated small-animal ultrasound screening and PET imaging to build up a preclinical trial platform. We characterized the tumor latency and progression in the hemizygous Th-MYCN mice, a genetically-engineered mouse model of NB. In parallel to human NB with MYCN amplification, the majority (75%) of Th-MYCN murine NB tumors showed higher uptake of FDG and lower uptake of FDOPA. Using the imaging platform, We have validated the potent therapeutic effect of epigenetic inhibition of MYCN transcription by targeting the bromodomain BRD4 reader protein, while 13-cis-retinoic acid showed no anti-tumor activity in this model. In conclusion, the functional FDG and FDOPA PET imaging characterizes the NB tumor behavior; complements the current risk stratification systems of NB; and serves as an important part of preclinical trails. The results of this study can be translated into critical clinical knowledge of molecular imaging of NB, and may pave the way of individualized target therapy through molecular imaging.
Subjects
Childhood cancer
neuroblastoma
positron emission tomography
molecular imaging
Th-MYCN transgenic mice
SDGs
Type
thesis
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