Xiang Xu1,2, Jiadi Xu1,2, Linda Knutsson1,3, Jing Liu1,4, Huanling Liu1,5, Yuguo Li1,2, Bachchu Lal6, John Laterra6,7, Dmitri Artemov1,8, Guanshu Liu1,2, Peter C M van Zijl1,2, Kannie W Y Chan1,9. 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medicine, Baltimore, Maryland. 2. FM Kirby Research Center, Kennedy Krieger Institute, Johns Hopkins Medicine, Baltimore, Maryland. 3. Department of Medical Radiation Physics, Lund University, Lund, Sweden. 4. Department of Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China. 5. Department of Ultrasound, Guangzhou Panyu Central Hospital, Panyu, People's Republic of China. 6. Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland. 7. Department of Oncology and Neuroscience, Johns Hopkins Medicine, Baltimore, Maryland. 8. JHU In Vivo Cellular Molecular Imaging Center, Johns Hopkins University Medicine, Baltimore, Maryland. 9. Department of Biomedical Engineering, City University of Hong Kong, Kowloon Tong, Hong Kong.
Abstract
PURPOSE: The mammalian target of rapamycin is an enzyme that regulates cell metabolism and proliferation. It is up-regulated in aggressive tumors, such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose CEST signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment; thus, glucose CEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment. METHODS: A human U87-EGFRvIII xenograft model in mice was studied. The mice were treated with a mammalian target of Rapamycin inhibitor, rapamycin. The effect of the treatment was evaluated in vivo with dynamic glucose CEST MRI. RESULTS: Rapamycin treatment led to significant increases (P < 0.001) in dynamic glucose-enhanced signal in both the tumor and contralateral brain as compared to the no-treatment group, namely a maximum enhancement of 3.7% ± 2.3% (tumor, treatment) versus 1.9% ± 0.4% (tumor, no-treatment), 1.7% ± 1.1% (contralateral, treatment), and 1.0% ± 0.4% (contralateral, no treatment). Dynamic glucose-enhanced contrast remained consistently higher in treatment versus no-treatment groups for the duration of the experiment (17 min). This was confirmed with area-under-curve analysis. CONCLUSION: Increased glucose CEST signal was found after mammalian target of Rapamycin inhibition treatment, indicating potential for dynamic glucose-enhanced MRI to study tumor response to glucose deprivation treatment.
PURPOSE: The mammalian target of rapamycin is an enzyme that regulates cell metabolism and proliferation. It is up-regulated in aggressive tumors, such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose CEST signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment; thus, glucose CEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment. METHODS: A human U87-EGFRvIII xenograft model in mice was studied. The mice were treated with a mammalian target of Rapamycin inhibitor, rapamycin. The effect of the treatment was evaluated in vivo with dynamic glucose CEST MRI. RESULTS:Rapamycin treatment led to significant increases (P < 0.001) in dynamic glucose-enhanced signal in both the tumor and contralateral brain as compared to the no-treatment group, namely a maximum enhancement of 3.7% ± 2.3% (tumor, treatment) versus 1.9% ± 0.4% (tumor, no-treatment), 1.7% ± 1.1% (contralateral, treatment), and 1.0% ± 0.4% (contralateral, no treatment). Dynamic glucose-enhanced contrast remained consistently higher in treatment versus no-treatment groups for the duration of the experiment (17 min). This was confirmed with area-under-curve analysis. CONCLUSION: Increased glucose CEST signal was found after mammalian target of Rapamycin inhibition treatment, indicating potential for dynamic glucose-enhanced MRI to study tumor response to glucose deprivation treatment.
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