PMID- 24151539
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20131023
LR  - 20211021
IS  - 1936-5233 (Print)
IS  - 1936-5233 (Electronic)
IS  - 1936-5233 (Linking)
VI  - 6
IP  - 5
DP  - 2013
TI  - (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.
PG  - 586-95
AB  - AIM: 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.
FAU - Lheureux, Stephanie
AU  - Lheureux S
AD  - Normandie Universite, Caen, France ; UNICAEN, BioTICLA EA 4656, Francois Baclesse 
      Cancer Centre, Caen, France ; Oncology Department, Francois Baclesse Cancer 
      Centre, Caen, France.
FAU - Lecerf, Charlotte
AU  - Lecerf C
FAU - Briand, Melanie
AU  - Briand M
FAU - Louis, Marie-Helene
AU  - Louis MH
FAU - Dutoit, Soizic
AU  - Dutoit S
FAU - Jebahi, Abdelghani
AU  - Jebahi A
FAU - Giffard, Florence
AU  - Giffard F
FAU - Fournier, Cecile Blanc
AU  - Fournier CB
FAU - Batalla, Alain
AU  - Batalla A
FAU - Poulain, Laurent
AU  - Poulain L
FAU - Aide, Nicolas
AU  - Aide N
LA  - eng
PT  - Journal Article
DEP - 20131001
PL  - United States
TA  - Transl Oncol
JT  - Translational oncology
JID - 101472619
PMC - PMC3799200
EDAT- 2013/10/24 06:00
MHDA- 2013/10/24 06:01
PMCR- 2013/10/01
CRDT- 2013/10/24 06:00
PHST- 2013/01/02 00:00 [received]
PHST- 2013/07/21 00:00 [revised]
PHST- 2013/07/24 00:00 [accepted]
PHST- 2013/10/24 06:00 [entrez]
PHST- 2013/10/24 06:00 [pubmed]
PHST- 2013/10/24 06:01 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - 13100 [pii]
AID - 10.1593/tlo.13100 [doi]
PST - epublish
SO  - Transl Oncol. 2013 Oct 1;6(5):586-95. doi: 10.1593/tlo.13100. eCollection 2013.