Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small c

E schematic of 2 h 2 o labeling to measure fasyn in

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( e ) Schematic of 2 H 2 O labeling to measure FASyn in A549 lung tumors (n=4 mice per treatment). ( f ) Fractional de novo palmitate (C16:0) and stearate (C18:0) synthesis (left) and maximal synthesis flux rate (right) is shown in A549 lung tumors (n=12 tumors per treatment) ( g ) Schematic of ND-646 trial design in A549 xenograft lung tumors. ( h ) Growth of A549 lung tumors treated with vehicle BID (n=9 mice), ND-646 50 mg/kg BID (n=7 mice), or 100 mg/kg BID (n=9 mice) or Carboplatin (n=9 mice). ( i ) Quantitation of tumor area as a percentage of total lung area. Average tumor area per treatment is shown. Svensson et al. Page 26 Nat Med . Author manuscript; available in PMC 2017 March 19. Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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Numbers in graphs ( c , f , i ) represent percent decrease compared to vehicle control. All values are expressed as means ± s.e.m. * P<0.05 ** P<0.01 *** P<0.001 relative to vehicle control determined by two sided student t test. Experiments were performed once for each assay. Svensson et al. Page 27 Nat Med . Author manuscript; available in PMC 2017 March 19. Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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Figure 5. ND-646 inhibits FASyn in lung tumors of Kras G12D p53 −/− and Kras G12D Lkb1 −/− mouse models of NSCLC and lowers plasma free fatty acids ( a ) Schematic of 2 H 2 O labeling to quantitate FASyn in KP luc and KL luc autochthonous lung tumors (n= 4–5 mice per treatment). ( b ) Maximal synthesis rate of palmitate (C16:0) and stearate (C18:0) in KP luc lung tumors (left) and KL luc lung tumors (right) after 1 week of ND-646 treatment (PO). 3 tumors per mouse were analyzed. Total number of tumors analyzed is shown in graph. Numbers above bars represent percent decrease compared to vehicle treatment. ( c ) Quantitation of individual free fatty acids (FFA) in KP luc lung tumors and ( d ) KL luc lung tumors. Left panel shows high abundance FFAs and right panel shows low abundance FFAs. ( e ) Quantitation of individual free fatty acids (FFA) in plasma from KP luc and ( f ) KL luc mice. Left panel shows high abundance FFAs and right panel shows low abundance FFAs. Svensson et al. Page 28 Nat Med . Author manuscript; available in PMC 2017 March 19. Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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Number of tumors and plasma samples analyzed per experiment are shown in graphs. Experiments were performed once for each assay. All values are expressed as means ± s.e.m. * P<0.05 ** P<0.01 *** P<0.001 relative to vehicle treatment determined by two sided student t test. # Represents p values >0.05 p <0.1. Exact p values ( c f ) and % reduction in FFAs are shown in Supplementary Fig. 5e–f. Svensson et al. Page 29 Nat Med . Author manuscript; available in PMC 2017 March 19. Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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Figure 6. ND-646 suppresses Kras G12D p53 −/− and Kras G12D Lkb1 −/− autochthonous NSCLC tumor growth ( a ) Schematic of ND-646 pre-clinical trial design in Kras G12D/+ p53 fl/fl (KP luc ) and Kras G12D/+ LKB1 fl/fl (KL luc ) genetic NSCLC tumor models ( b ) Bioluminescence overlay images of ND-646 efficacy in KP luc (left) and KL luc (right) lung tumors. Images are representative for each treatment condition. Scale bar = 1cm.
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  • Winter '19
  • Robert S Kiss
  • Fatty acid metabolism, Nat Med, FASyn

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