title: Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma.
abstract: OBJECTIVE
  We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of11C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo EXPERIMENTAL DESIGN: Acetate fate tracking using13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using11C-acetate-PET/CT imaging and tissue biodistribution.
  
  
  RESULTS
  In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo,11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise,11C-acetate uptake was significantly reduced in MM tumors after treatment.
  
  
  CONCLUSIONS
  Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability.11C-Acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease.11C-Acetate-PET also detected response to therapy in vivo Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that11C-acetate-PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416-29. ©2016 AACR.
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fontana
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Xia
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Deep
authors.initials: D
authors.lastname: Hathi
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Xiang
authors.affiliation: San Raffaele Scientific Institute (SRSI), Division of Genetics and Cell Biology, and Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Cenci
authors.affiliation: Department of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Kooresh I
authors.initials: KI
authors.lastname: Shoghi
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Akers
authors.affiliation: Department of Chemistry, Washington University, St. Louis, Missouri.
authors.forename: Andre
authors.initials: A
authors.lastname: D'avignon
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri. mshokeen@wustl.edu kweilbae@wustl.edu.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
authors.affiliation: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri. mshokeen@wustl.edu kweilbae@wustl.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Shokeen
mesh_terms: D000085:Acetates / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D019788:Fluorodeoxyglucose F18 / Q000627:therapeutic use; D006801:Humans; D050356:Lipid Metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D009101:Multiple Myeloma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D000085:Acetates; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18