title: (18)F-FDG Is a Surrogate Marker of Therapy Response and Tumor Recovery after Drug Withdrawal during Treatment with a Dual PI3K/mTOR Inhibitor in a Preclinical Model of Cisplatin-Resistant Ovarian Cancer.
abstract: OBJECTIVE
  Targeting the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming chemoresistance in ovarian cancer. We investigated the capability of (18)F-fluororodeoxyglucose ((18)F-FDG) small-animal positron emission tomography (SA-PET) to predict the effects of a dual PI3K/mTOR inhibitor (BEZ-235) in a cisplatin-resistant ovarian cancer model.
  
  
  METHODS
  In a first experiment, nude rats bearing subcutaneous SKOV3 tumors received BEZ-235 for 3 days given alone or after paclitaxel and were compared to controls (either untreated or that were given the excipients of paclitaxel and BEZ-235). SA-PET was performed at baseline, on day 3, and day 7. In a second experiment aiming at further exploring the kinetics of (18)F-FDG tumor uptake during the first 48 hours following drug cessation, untreated controls were compared to rats receiving BEZ-235, which were imaged at baseline, on day 3, on day 4, and on day 5. SA-PET results were compared to cell proliferation assessment (Ki-67), PI3K/mTOR downstream target expression studies (pAKT and phospho-eukaryotic translation initiation factor 4E-binding protein 1), and apoptosis evaluation (cleaved caspase-3).
  
  
  RESULTS
  In the first experiment, BEZ-235, compared to untreated controls, induced a marked decrease in (18)F-FDG uptake on day 3, which was correlated to a significant decrease in cell proliferation and to a significant PI3K/mTOR pathway inhibition. No tumor necrosis or apoptosis occurred. Four days following treatment cessation, tumor recovery (in terms of PI3K/mTOR inhibition and cell proliferation) occurred and was identified by (18)F-FDG SA-PET. Paclitaxel plus BEZ-235 showed results similar to BEZ-235 alone. In the second experiment, PI3K/mTOR pathways exhibited partial recovery as early as 24 hours following treatment cessation, but both (18)F-FDG SA-PET and cell proliferation remained unchanged.
  
  
  CONCLUSIONS
  (18)F-FDG SA-PET is a surrogate marker of target inhibition during treatment with BEZ-235 and predicts tumor recovery 4 days after drug withdrawal, but not during the first 48 hours following drug cessation, when a lag between PI3K/mTOR pathway recovery and metabolic recovery is observed. (18)F-FDG SA-PET could be used for therapy monitoring of PI3K/mTOR inhibitors, but our results also raise questions regarding the potential impact of the delay between PET imaging and the last drug intake on the accuracy of FDG imaging.
authors.affiliation: Normandie Université, Caen, France ; UNICAEN, BioTICLA EA 4656, Francois Baclesse Cancer Centre, Caen, France ; Oncology Department, Francois Baclesse Cancer Centre, Caen, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lheureux
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lecerf
authors.forename: Mélanie
authors.initials: M
authors.lastname: Briand
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Louis
authors.forename: Soizic
authors.initials: S
authors.lastname: Dutoit
authors.forename: Abdelghani
authors.initials: A
authors.lastname: Jebahi
authors.forename: Florence
authors.initials: F
authors.lastname: Giffard
authors.forename: Cécile Blanc
authors.initials: CB
authors.lastname: Fournier
authors.forename: Alain
authors.initials: A
authors.lastname: Batalla
authors.forename: Laurent
authors.initials: L
authors.lastname: Poulain
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aide