Award Number : W 81 XWH - 06 - 1 - 0494 TITLE : Malonyl - CoA Decarboxylase ( MCD ) as a Potential Therapeutic Target for Breast Cancer PRINCIPAL INVESTIGATOR :

F atty a cid s ynthase ( FAS) inhibition initiates selective ap optosis o f can cer cel ls b oth in vivo and in vitro, which m ay i nvolve malonyl-CoA metabolism. T hese findings l ed to exploration of malonyl-CoA decarboxylase ( MCD) as a p otential novel target for cancer treatment. M CD regulates the levels of cellular malonyl-CoA through the decarboxylation of malonyl-CoA to acetyl-CoA. Malonyl-CoA is both a s ubstrate f or F AS a nd a n i nhibitor o f f atty a cid o xidation a cting a s a metabolic switch between anabolic fatty acid synthesis a nd catabolic fatty acid o xidation. W e n ow r eport t hat t reatment o f h uman b reast can cer ( MCF7) cel ls w ith M CD s mall i nterference RNA (siRNA) reduces MCD expression and activity, reduces ATP levels, and is cytotoxic to MCF7 cells, but not to human fibroblasts. In addition, we s ynthesized a s mall m olecule i nhibitor o f M CD, 5 -{(Morpholine-4-carbonyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)phenyl]-amino}-pentanoic acid methyl ester (MPA). S imilar to MCD siRNA, MPA inhibits MCD activity in MCF7 cells, increases cellular malonyl-CoA levels and is cytotoxic to a n umber of human breast cancer cell lines in vitro. T aken together, these data indicate that MCDinduced c ytotoxicity i s l ikely m ediated t hrough malonyl-CoA metabolism. T hese findings s upport the hypothesis that MCD i s a p otential therapeutic target for cancer therapy. 14. SUBJECT TERMS Malonyl-CoA Decarboxylase, malonyl-CoA, siRNA 15. NUMBER OF PAGES 19 16. PRICE CODE 17. SECURITY CLASSIFICATION OF REPORT Unclassified 18. SECURITY CLASSIFICATION OF THIS PAGE Unclassified 19. SECURITY CLASSIFICATION OF ABSTRACT Unclassified 20. LIMITATION OF ABSTRACT Unlimited NSN 7540-01-280-5500 Standard Form 298 (Rev. 2-89) Prescribed by ANSI Std. Z39-18 298-102