Evaluating acetate metabolism for imaging and targeting in multiple myeloma

F Fontana, X Ge, X Su, D Hathi, J Xiang, S Cenci, R Civitelli, KI Shoghi, WJ Akers, A D'avignon, KN Weilbaecher, M Shokeen

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: 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 of 11C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo. Experimental design: Acetate fate tracking using 13C-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 using 11C-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, 11Cacetate 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 that 11C-acetate-PET is a promising imaging modality for MM. © 2016 AACR.
Original languageEnglish
Pages (from-to)416-429
Number of pages14
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
Publication statusPublished - 2017

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Multiple Myeloma
Acetates
Positron-Emission Tomography
Bone and Bones
Lipids
Cell Survival
Magnetic Resonance Spectroscopy
Neoplasms
Intracellular Membranes
Poisons
Bone Diseases
Membrane Lipids
Cell Biology
carbon-11 acetate
B-Lymphocytes
Research Design
Therapeutics
Cell Membrane
Pharmacology
Muscles

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Evaluating acetate metabolism for imaging and targeting in multiple myeloma. / Fontana, F; Ge, X; Su, X; Hathi, D; Xiang, J; Cenci, S; Civitelli, R; Shoghi, KI; Akers, WJ; D'avignon, A; Weilbaecher, KN; Shokeen, M.

In: Clinical Cancer Research, Vol. 23, No. 2, 2017, p. 416-429.

Research output: Contribution to journalArticle

Fontana, F, Ge, X, Su, X, Hathi, D, Xiang, J, Cenci, S, Civitelli, R, Shoghi, KI, Akers, WJ, D'avignon, A, Weilbaecher, KN & Shokeen, M 2017, 'Evaluating acetate metabolism for imaging and targeting in multiple myeloma', Clinical Cancer Research, vol. 23, no. 2, pp. 416-429. https://doi.org/10.1158/1078-0432.CCR-15-2134
Fontana, F ; Ge, X ; Su, X ; Hathi, D ; Xiang, J ; Cenci, S ; Civitelli, R ; Shoghi, KI ; Akers, WJ ; D'avignon, A ; Weilbaecher, KN ; Shokeen, M. / Evaluating acetate metabolism for imaging and targeting in multiple myeloma. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 2. pp. 416-429.
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AU - Ge, X

AU - Su, X

AU - Hathi, D

AU - Xiang, J

AU - Cenci, S

AU - Civitelli, R

AU - Shoghi, KI

AU - Akers, WJ

AU - D'avignon, A

AU - Weilbaecher, KN

AU - Shokeen, M

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N2 - Purpose: 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 of 11C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo. Experimental design: Acetate fate tracking using 13C-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 using 11C-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, 11Cacetate 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 that 11C-acetate-PET is a promising imaging modality for MM. © 2016 AACR.

AB - Purpose: 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 of 11C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo. Experimental design: Acetate fate tracking using 13C-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 using 11C-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, 11Cacetate 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 that 11C-acetate-PET is a promising imaging modality for MM. © 2016 AACR.

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