509 THERAPEUTIC FATTY ACID SYNTHASE INHIBITION IN PROSTATE CANCER AND THE USE OF 11C-ACETATE TO MONITOR THERAPEUTIC EFFECTS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (III)1 Apr 2013509 THERAPEUTIC FATTY ACID SYNTHASE INHIBITION IN PROSTATE CANCER AND THE USE OF 11C-ACETATE TO MONITOR THERAPEUTIC EFFECTS Greg Shaw, David Lewis, Joan Boren, Antonio Ramos-Montoya, Robert Bielik, Dmitry Soloviev, Brindle Kevin, and Neal David Greg ShawGreg Shaw Cambridge, United Kingdom More articles by this author , David LewisDavid Lewis Cambridge, United Kingdom More articles by this author , Joan BorenJoan Boren Cambridge, United Kingdom More articles by this author , Antonio Ramos-MontoyaAntonio Ramos-Montoya Cambridge, United Kingdom More articles by this author , Robert BielikRobert Bielik Cambridge, United Kingdom More articles by this author , Dmitry SolovievDmitry Soloviev Cambridge, United Kingdom More articles by this author , Brindle KevinBrindle Kevin Cambridge, United Kingdom More articles by this author , and Neal DavidNeal David Cambridge, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1903AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Fatty acid synthase(FAS) is upregulated in prostate cancer at mRNA and protein levels and is linked to prognosis. Clinical FAS inhibition is a rational therapeutic target and the development of a biomarker by which to monitor therapeutic effect is attractive. METHODS Prostate cancer C42b cell xenografts were generated in Nod-SCID-gamma mice. The mice were dosed daily by oral gavage with 3mg/kg GSK2194069, a novel FAS inhibitor or vehicle. Mice bearing xenografts were injected with 11C acetate and imaged using PET CT before and after oral administration of GSK2194069 3mg/kg. Similar animals were administered 14C acetate before and after GSK2194069 administration. Gas chromatography/Mass spectrometry was used to quantify fatty acid content of tumours before and after GSK2194069 administration. RESULTS Tumour growth was inhibited in those mice dosed with GSK2194069. Mean tumour size after 5 weeks growth was 595.0 ± 171.2mm3 (N=6) in the vehicle group (and 106.2 ± 26.23mm3 (N=5) in the GSK2194069 treated group (p=0.037 two-tailed unpaired t-test). There was no significant weight loss in the GSK2194069 treated cohort and no adverse effects noted. The effect of GSK2194069 in decreasing acetate uptake was seen with scintillation detection of 14C-acetate in the lipid phase of C42b xenograft tumours by 56% 2 hours after dosing with GSK2194069. Inhibition of FAS by GSK2194069 resulted in a decrease in acetate signal in all animals (n=7) and by a median of 43 percent (p<0.05, paired t-test). CONCLUSIONS PC xenograft growth can be inhibited with GSK2194069 a novel FAS inhibitor. The effects of GSK2194069 on FAS activity can be monitored non-invasively by imaging with 11C acetate PET. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e208-e209 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Greg Shaw Cambridge, United Kingdom More articles by this author David Lewis Cambridge, United Kingdom More articles by this author Joan Boren Cambridge, United Kingdom More articles by this author Antonio Ramos-Montoya Cambridge, United Kingdom More articles by this author Robert Bielik Cambridge, United Kingdom More articles by this author Dmitry Soloviev Cambridge, United Kingdom More articles by this author Brindle Kevin Cambridge, United Kingdom More articles by this author Neal David Cambridge, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...