ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)
Acetate metabolism in Multiple Myeloma identifies 11C-Acetate PET as a novel strategy to image bone disease and response to treatment in preclinical models
Francesca Fontana 1 , Xia Ge 1 , Xinming Su 1 , Jingyu Xiang 1 , Simone Cenci 3 , Roberto Civitelli 1 , Kooresh Shoghi 1 , Walter Akers 1 , Andre D’Avignon 2 , Monica Shokeen 1 & Katherine Weilbaecher 1
1Washington University School of Medicine, St Louis, Missouri, USA; 2Washington University, St Louis, Missouri, USA; 3San Raffaele Scientific Institute (SRSI), Milano, Italy.
Multiple Myeloma (MM) is a malignancy of Plasma Cells (PC), characterized by severe osteolytic lesions but poor 99Tc-MDP uptake in bone scans due to osteoblast inhibition. We hypothesized that high demands for membrane biosynthesis in tumour PC would enhance monocarboxylic acid anabolism and uptake, which could be exploited for treatment and molecular imaging. Here, we tested the efficacy of clinically available 11C-Acetate PET to detect myeloma and quantitatively image treatment response in vivo, and characterized acetate metabolism in myeloma cells (MMC).
Experimental design: 11C-Acetate PET/CT imaging and bio-distribution were performed in subcutaneous (5TGM1, U266 and OPM2) and orthotopic (KaLwRij) MM mouse models. Tumour burden was quantified by flow cytometry, optical imaging, and serum electrophoresis (SPEP). Mice with established MM were treated with bortezomib to evaluate response with PET. In order to study acetate metabolism, we performed metabolite fate tracking with 13C-edited 1H NMR and challenged cells with chemical inhibitors of transport (CHC) or anabolism (orlistat) to assess single-agent or combined antimyeloma effects.
Results: 11C-Acetate uptake was enhanced in subcutaneous MMC tumours. Tumour-bearing leg bones showed higher 11C-Acetate uptake than unaffected bones or muscle. Post treatment, 11C-Acetate uptake was significantly decreased, demonstrating response. NMR showed metabolism of acetate by MMC, including incorporation into membrane lipids. Inhibition of acetate metabolism had limited effects on normal B cells and bone resident cells (osteoblasts, osteoclasts, BMSC), but induced cell death in MMC.
Conclusions: In vitro uptake of acetate from the extracellular environment is enhanced in MMC to sustain growth and viability. 11C-Acetate PET detected the presence of myeloma cells in vivo in MM mouse models, including intramedullary disease. 11C-Acetate-PET rapidly detected response to therapy in vivo. Our data suggest that 11C-Acetate PET might be a promising tool for imaging in MM, and anabolic metabolism of monocarboxylic acids could represent a novel therapeutic target.
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