Monitoring Therapy with MEK Inhibitor U0126 in a Novel Wilms Tumor Model in Wt1 Knockout Igf2 Transgenic Mice Using 18F-FDG PET with Dual-Contrast Enhanced CT and MRI: Early Metabolic Response Without Inhibition of Tumor Growth

• Published in: Molecular imaging and biology 2013-04, Vol.15 (2), p.175-185
• Main Authors: Flores, Leo G., Yeh, Hsin-Hsien, Soghomonyan, Suren, Young, Daniel, Bankson, James, Hu, Qianghua, Alauddin, Mian, Huff, Vicki, Gelovani, Juri G.
• Format: Article
• Language: English
• Subjects: Animals; Butadienes - pharmacology; Female; Fluorodeoxyglucose F18; Imaging; Immunohistochemistry; Magnetic Resonance Imaging - methods; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Multimodal Imaging - methods; Nitriles - pharmacology; Positron-Emission Tomography; Radiology; Research Article; Tomography, X-Ray Computed; Wilms Tumor - diagnosis; Wilms Tumor - diagnostic imaging; Wilms Tumor - drug therapy; Wilms Tumor - pathology
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-012-0588-5

Purpose The understanding of the role of genetic alterations in Wilms tumor development could be greatly advanced using a genetically engineered mouse models that can replicate the development and progression of this disease in human patients and can be monitored using non-invasive structural and molecular imaging optimized for renal tumors. Procedures Repetitive dual-contrast computed tomography (CT; intravenous and intraperitoneal contrast), T2-weighted magnetic resonance imaging (MRI), and delayed 2-deoxy-2-[ 18 F]fluoro- d -glucose ( 18 F-FDG) positron emission tomography (PET) were utilized for characterization of Igf2 biallelic expression/ Wt1 knockout mouse model of Wilms tumor. For CT imaging, Ioversol 678 mg/ml in 200 μl was administered i.p. followed by 100 μl injected intravenously at 20 and 15 min prior to imaging, respectively. Static PET imaging studies were acquired at 1, 2, and 3 h after i.v. administration of 18 F-FDG (400 μCi). Coronal and sagittal T1-weighted images (T E /T R 8.5/620 ms) were acquired before and immediately after i.v. injection of 0.4 ml/kg gadopentetate dimeglumine followed by T2-weighted images (T E /T R 60/300 ms). Tumor tissue samples were characterized by histopathology and immunohistochemistry for Glut1, FASN, Ki67, and CD34. In addition, six Wt1-Igf2 mice were treated with a mitogen-activated protein kinase (MEK) inhibitor U0126 (50 μmol/kg i.p.) every 4 days for 6 weeks. 18 F-FDG PET/CT imaging was repeated at different days after initiation of therapy with U0126. The percent change of initial tumor volume and SUV was compared to non-treated historic control animals. Results Overall, the best tumor-to-adjacent kidney contrast as well as soft tissue contrast for other abdominal organs was achieved using T2-weighted MRI. Delayed 18 F-FDG PET (3-h post 18 F-FDG administration) and dual-contrast CT (intravenous and intraperitoneal contrast) provided a more accurate anatomic and metabolic characterization of Wilms tumors in Wt1-Igf2 mice during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50–100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R