PET with 18F-FLT can monitor early response to treatment for cisplatin-resistant ovarian tumors by mTOR inhibitors, according to research reported in this month's Journal of Nuclear Medicine.
The chemotherapy drug cisplatin is often effective against ovarian cancer when first given; however, tumors can become resistant to the drug and start growing again, so the need for second-line therapies is pressing. One potential way to overcome cisplatin resistance is to target the mammalian target of rapamycin (mTOR) pathway. The aim of the study was to evaluate the ability of 18F-FLT, a PET probe for cell proliferation, to predict early response to everolimus (an mTOR inhibitor) in a mouse model of subcutaneously transplanted human cisplatin-resistant ovarian cancer.
BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle, and 18F-FLT PET was performed at baseline, day 2, and day 7 by Nicolas Aide, MD, Centre for Molecular Imaging at the Peter MacCallum Cancer Centre in East Melbourne, Australia, and colleagues.
18F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect by the researchers. The ex vivo analysis included bromodeoxyuridine incorporation as a marker of cell proliferation, and phosphorylation of ribosomal protein S6 as a downstream marker of mTOR activation.
During the treatment period, no significant change in tumor 18F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, 18F-FLT SUVmean decreased by 33 percent at day two and 66 percent at day seven, compared with baseline. Notably, the reduction of 18F-FLT uptake observed at day two in the everolimus group preceded changes in tumor volume, and a significant difference in 18F-FLT uptake was observed between vehicle and drug-treated tumors at both day two and day seven.
"PET imaging could be used to evaluate the treatment's efficacy very early after treatment initiation—at a time when conventional criteria based on tumor size measurements are useless," said Aide.
Correlative immunohistochemistry showed a marked decrease in ribosomal protein S6 activity and bromodeoxyuridine incorporation corresponding to the decreased level of 18F-FLT uptake, according to Aide and colleagues.
The study showed that 18F-FLT PET was able to predict early response to mTOR inhibition in a cisplatin-resistant ovarian cancer in mice. The researchers suggest that this technique should be considered for therapeutic assessment in humans. They also point out the technique's potential to non-invasively and longitudinally monitor the efficacy of combination therapy.
“Aide and colleagues present an important preclinical study on 18F-FLT PET after mTOR inhibition in a cisplatin-resistant ovarian tumor model,” wrote Marijke De Saint-Hubert, PhD student in the department of nuclear medicine at the University Hospital Gasthuisberg, Leuven, Belgium, and other authors on an invited perspective article in the same issue of JNM.
Current evidence suggests that 18F-FLT monitoring is more likely to be successful in patients undergoing cytostatic therapy. This possibility will have to be evaluated in larger clinical trials for different tumor entities, concluded De Saint-Hubert and other authors.