title: Examining changes in [18 F]FDG and [18 F]FLT uptake in U87-MG glioma xenografts as early response biomarkers to treatment with the dual mTOR1/2 inhibitor AZD8055.
abstract: OBJECTIVE
  The mTOR kinase inhibitor AZD8055 inhibits both mTORC1 and mTORC2 leading to disruption of glucose metabolism and proliferation pathways. This study assessed the impact of single and multiple doses of AZD8055 on the uptake of the glucose metabolism marker 2-deoxy-2-[(18) F]fluoro-D-glucose ([(18) F]FDG) and the proliferation marker 3'-deoxy-3'-[(18) F]fluorothymidine ([(18) F]FLT) in U87-MG glioma xenografts.
  
  
  METHODS
  Mice bearing U87-MG tumours received either vehicle or AZD8055 (20 mg/kg) once daily p.o. Mice were imaged with either [(18) F]FDG or [(18) F]FLT PET to assess treatment response. Comparisons were made between in vivo imaging and ex vivo histopathology data.
  
  
  RESULTS
  Tumour uptake of [(18) F]FDG was reduced by 33 % 1 h after a single dose of AZD8055 and by 49 % following 4 days of dosing. These changes coincided with suppression of the mTOR pathway biomarkers pS6 and pAKT. In contrast, the effect of AZD8055 on [(18) F]FLT uptake was inconsistent.
  
  
  CONCLUSIONS
  The very rapid change in [(18) F]FDG uptake following acute AZD8055 treatment suggests that this could be used as an early mechanistic biomarker of metabolic changes resulting from mTOR inhibition. The utility of [(18) F]FLT for measuring the anti-proliferative effect of AZD8055 remains unclear.
authors.affiliation: Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK, heather.keen@astrazeneca.com.
authors.forename: Heather G
authors.initials: HG
authors.lastname: Keen
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Ricketts
authors.forename: Juliana
authors.initials: J
authors.lastname: Maynard
authors.forename: Armelle
authors.initials: A
authors.lastname: Logie
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.forename: Aoife M
authors.initials: AM
authors.lastname: Shannon
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Guichard
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000493:pharmacokinetics*
chemical_list: D014408:Biomarkers, Tumor; D009025:Morpholines; D019788:Fluorodeoxyglucose F18; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D058570:TOR Serine-Threonine Kinases