Kemp H Kernstine1, Brandon Faubert2, Quyen N Do3, Thomas J Rogers2, Christopher T Hensley2, Ling Cai4, Jose Torrealba5, Dwight Oliver5, Jason W Wachsmann3, Robert E Lenkinski6, Craig R Malloy7, Ralph J Deberardinis8. 1. Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern, Dallas, Texas. Electronic address: kemp.kernstine@utsouthwestern.edu. 2. Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas. 3. Department of Radiology, University of Texas Southwestern, Dallas, Texas. 4. Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas; Quantitative Biomedical Research Center, University of Texas Southwestern, Dallas, Texas. 5. Department of Pathology, University of Texas Southwestern, Dallas, Texas. 6. Department of Radiology, University of Texas Southwestern, Dallas, Texas; Advanced Imaging Research Center, University of Texas Southwestern, Dallas, Texas. 7. Department of Radiology, University of Texas Southwestern, Dallas, Texas; Advanced Imaging Research Center, University of Texas Southwestern, Dallas, Texas; Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas. 8. Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas; Department of Pediatrics, University of Texas Southwestern, Dallas, Texas; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern, Dallas, Texas; Howard Hughes Medical Institute, Chevy Chase, Maryland.
Abstract
BACKGROUND: In non-small cell lung cancer (NSCLC), 18fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One variable of FDG-PET, the maximum standard uptake value (SUVm), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. This study used stable glucose isotope tracing to determine whether the SUVm predicts glycolytic metabolism or other glucose fates in tumors. METHODS: In this prospective Institutional Review Board-approved clinical trial, 52 untreated potentially resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During the surgical procedure, the patients were infused with 13C-labeled glucose. Blood, tumor, and normal lung samples were analyzed by mass spectrometry to determine 13C enrichment in glycolytic intermediates. These values were compared with clinical variables, including SUVm, maximum tumor diameter, stage, grade, and MIB-1/Ki67 proliferation index. RESULTS: For each patient, 13C enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUVm did not correlate with glycolytic intermediate labeling. Rather, SUVm correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index. CONCLUSIONS: SUVm does not correlate with glycolytic metabolism in human NSCLC but does correlate with the proliferation index, suggesting that SUVm predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUVm, tumor metabolism, and therapeutic vulnerabilities in human NSCLCs.
BACKGROUND: In non-small cell lung cancer (NSCLC), 18fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One variable of FDG-PET, the maximum standard uptake value (SUVm), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. This study used stable glucose isotope tracing to determine whether the SUVm predicts glycolytic metabolism or other glucose fates in tumors. METHODS: In this prospective Institutional Review Board-approved clinical trial, 52 untreated potentially resectable confirmed NSCLCpatients underwent FDG-PET computed tomography. During the surgical procedure, the patients were infused with 13C-labeled glucose. Blood, tumor, and normal lung samples were analyzed by mass spectrometry to determine 13C enrichment in glycolytic intermediates. These values were compared with clinical variables, including SUVm, maximum tumor diameter, stage, grade, and MIB-1/Ki67 proliferation index. RESULTS: For each patient, 13C enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUVm did not correlate with glycolytic intermediate labeling. Rather, SUVm correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index. CONCLUSIONS: SUVm does not correlate with glycolytic metabolism in humanNSCLC but does correlate with the proliferation index, suggesting that SUVm predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUVm, tumor metabolism, and therapeutic vulnerabilities in humanNSCLCs.
Authors: Kathryn E Wellen; Chao Lu; Anthony Mancuso; Johanna M S Lemons; Michael Ryczko; James W Dennis; Joshua D Rabinowitz; Hilary A Coller; Craig B Thompson Journal: Genes Dev Date: 2010-11-24 Impact factor: 11.361
Authors: Elena Piskounova; Michalis Agathocleous; Malea M Murphy; Zeping Hu; Sara E Huddlestun; Zhiyu Zhao; A Marilyn Leitch; Timothy M Johnson; Ralph J DeBerardinis; Sean J Morrison Journal: Nature Date: 2015-10-14 Impact factor: 49.962
Authors: Justin Goodwin; Michael L Neugent; Shin Yup Lee; Joshua H Choe; Hyunsung Choi; Dana M R Jenkins; Robin J Ruthenborg; Maddox W Robinson; Ji Yun Jeong; Masaki Wake; Hajime Abe; Norihiko Takeda; Hiroko Endo; Masahiro Inoue; Zhenyu Xuan; Hyuntae Yoo; Min Chen; Jung-Mo Ahn; John D Minna; Kristi L Helke; Pankaj K Singh; David B Shackelford; Jung-Whan Kim Journal: Nat Commun Date: 2017-05-26 Impact factor: 14.919
Authors: Rodrigo Romero; Volkan I Sayin; Shawn M Davidson; Matthew R Bauer; Simranjit X Singh; Sarah E LeBoeuf; Triantafyllia R Karakousi; Donald C Ellis; Arjun Bhutkar; Francisco J Sánchez-Rivera; Lakshmipriya Subbaraj; Britney Martinez; Roderick T Bronson; Justin R Prigge; Edward E Schmidt; Craig J Thomas; Chandra Goparaju; Angela Davies; Igor Dolgalev; Adriana Heguy; Viola Allaj; John T Poirier; Andre L Moreira; Charles M Rudin; Harvey I Pass; Matthew G Vander Heiden; Tyler Jacks; Thales Papagiannakopoulos Journal: Nat Med Date: 2017-10-02 Impact factor: 53.440