title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 (TE/TR 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 (TE/TR 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 expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased (18)F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in (18)F-FDG SUV was observed, as compared to pre-treatment levels (p < 0.05, paired Student t test), which constitutes a metabolic response. Six weeks later, despite continuing therapy, the (18)F-FDG SUV increased again to previous levels.
  
  
  CONCLUSIONS
  The optimized dual contrast PET/CT imaging with early post i.v. and i.p. contrast CT and 3 h delayed PET imaging after (18)F-FDG administration provides a sensitive and reliable method for detecting early tumor lesions in this endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.
authors.affiliation: Department of Experimental Diagnostic Imaging, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Leo G
authors.initials: LG
authors.lastname: Flores
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Yeh
authors.forename: Suren
authors.initials: S
authors.lastname: Soghomonyan
authors.forename: Daniel
authors.initials: D
authors.lastname: Young
authors.forename: James
authors.initials: J
authors.lastname: Bankson
authors.forename: Qianghua
authors.initials: Q
authors.lastname: Hu
authors.forename: Mian
authors.initials: M
authors.lastname: Alauddin
authors.forename: Vicki
authors.initials: V
authors.lastname: Huff
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D005260:Female; D019788:Fluorodeoxyglucose F18; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D064847:Multimodal Imaging / Q000379:methods*; D009570:Nitriles / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D009396:Wilms Tumor / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology
chemical_list: D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D019788:Fluorodeoxyglucose F18; D020929:Mitogen-Activated Protein Kinase Kinases