title: [18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy.
abstract: OBJECTIVE
  Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models.
  
  
  METHODS
  Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1.
  
  
  RESULTS
  Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression.
  
  
  CONCLUSIONS
  FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Heather
authors.initials: H
authors.lastname: Jacene
authors.forename: Dongweon
authors.initials: D
authors.lastname: Song
authors.forename: Felip
authors.initials: F
authors.lastname: Vilardell
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Dan
authors.initials: D
authors.lastname: Laheru
authors.forename: Richard
authors.initials: R
authors.lastname: Wahl
authors.forename: Chris
authors.initials: C
authors.lastname: Endres
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D019788:Fluorodeoxyglucose F18; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018579:Patient Selection; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019275:Radiopharmaceuticals; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D051272:Glucose Transporter Type 1; D019275:Radiopharmaceuticals; C495677:SLC2A1 protein, human; D019788:Fluorodeoxyglucose F18; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus