Multiple myeloma imaging by C-11-acetate metabolic PET and in vitro metabolite fate mapping using isotope-edited NMR

1405 Objectives Multiple Myeloma (MM) is a malignancy of bone marrow (BM) plasma cells (PC) whose endoplasmic reticulum (ER) secretes massive amounts of immunoglobulins (Ig). Based on the high ER stress sustained by PC cells, we hypothesize that lipid metabolism would be a critical process for MM cells and that acetate could provide a readily-available substrate. Methods Immunocompetent, syngeneic C57Bl/KaLwRij mice were injected with 1 x 106 murine 5TGM1-GFP cells intravenously. At 3-week post tumor inoculation, mice were injected with 11C-acetate (3 MBq) for 30 min dynamic PET imaging. 18F-Sodium fluoride scans were performed for co-registration with the skeleton. Inveon Research Workstation (IRW) was used for image analysis. The same 5TGM1 or human MM cell lines (OPM2 and U266) were incubated with 13C-labeled acetate or glucose, and were analyzed by 1H and 13C-edited 1H NMR. Drug toxicity assays were conducted by incubating MM cells for 24 or 48 h with the fatty acid synthase (FASN) inhibitor Orlistat (10 to 500 µM) alone or in combination with tunicamycin (N-glycosilation inhibitor, 1mg/mL) or proteasome inhibitors (bortezomib or carflizomib 0.5-50 nM). Cell death was assessed upon Propidium Iodide staining. Results MM cells underwent cell death upon treatment with Orlistat. Synergistic effects were obtained by combining FASN inhibition with treatments that induce ER stress. The 1H/13C-NMR analysis demonstrated uptake of acetate accompanied by release of lactate. SUVs from mouse legs demonstrated differential uptake of 11C-acetate between tumor and naive mice (p Conclusions 11C-acetate consistently served as a PET marker for MM. MM cancer cells themselves take up acetate, the utilization of which, by FASN seems significant to MM cell viability and resistance to ER stress and treatment. Research Support NCI-NIH: R01 CA176221 (PI: Shokeen)