abstract (small animal testing)
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.
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.