¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

Abstract

Targeting the mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming cisplatin resistance in ovarian cancer patients. Because mTOR inhibition affects cell proliferation, we aimed to study whether 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) PET could be useful for monitoring early response to treatment with mTOR inhibitors in an animal model of cisplatin-resistant ovarian tumor. Methods: 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 18 F-FLT PET was performed at baseline, day 2, and day 7 of treatment. 18 F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect. Ex vivo immunohistochemistry studies were performed on separate cohorts of mice treated as above and sacrificed at the same time points as for the PET studies. 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. Results: During the treatment period, no significant change in tumor 18 F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, 18 F-FLT SUVmean decreased by 33% (P 5 0.003) at day 2 and 66% (P , 0.001) at day 7, compared with baseline. Notably, the reduction of 18 F-FLT uptake observed at day 2 in the everolimus group preceded changes in tumor volume, and a significant difference in 18 F-FLT uptake was observed between vehicle and drug-treated tumors at both day 2 (P 5 0.0008) and day 7 (P 5 0.01). In ex vivo studies, everolimus treatment resulted in a 98% reduction in phosphorylated ribosomal protein S6 immunostaining at day 2 (P 5 0.02) and 91% reduction at day 7 (P 5 0.003), compared with the vehicle group. Bromodeoxyuridine incorporation was reduced by 65% at day 2 (not significant) and by 41% at day 7 (P 5 0.02) in drug versus vehicle groups. Conclusion: Reduction in 18 F-FLT uptake correlates well with the level of mTOR inhibition by everolimus in the SKOV3 ovarian tumor model. These data suggest that early treatment monitoring by 18 F-FLT PET may be of use in future preclinical or clinical trials evaluating treatment of cisplatinresistant ovarian tumors by mTOR inhibitors.

Cardamonin enhances the anti-proliferative effect of cisplatin on ovarian cancer

“…In addition, mTOR is frequently hyper-activated in cisplatin-insensitive ovarian cancer cells (43). In the present study, it was demonstrated that the activation of mTOR and p70S6K was significantly inhibited by cardamonin, and cardamonin combined with cisplatin.…”

In Vivo Imaging of Cell Proliferation Enables the Detection of the Extent of Experimental Rheumatoid Arthritis by 3′-Deoxy-3′-18F-Fluorothymidine and Small-Animal PET

“…Because 18 F-FLT PET is frequently used in the pharmaceutical industry and by academic researchers to determine the response of anticancer drugs (29,(40)(41)(42), our imaging method may represent a useful tool for evaluating the impact of new therapeutics on cell proliferation both in experimental arthritis models and in humans. Additionally, PET/MR imaging and PET/CT are noninvasive techniques that enable longitudinal studies, allowing the investigation of a single subject at several time points.…”

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

“…In other preclinical studies, however, 18 F-FLT-PET was also capable to monitor (early) temsirolimus response and 18 F-FLT-PET is now being evaluated for monitoring mTOR-targeted therapies in the clinic (NCT01246817 and NCT01143779). 47,48 Although the exact value of 18 F-FLT-PET imaging during temsirolimus-targeted therapies in osteosarcoma patients remains to be established, a recently initiated clinical study in osteosarcomas aims to evaluate the indication of 18 F-FLT-PET imaging in determining tumor response after one cycle of neoadjuvant chemotherapy (NCT01882231). At present however, the use of 18 F-FLT-PET in osteosarcomas is still poorly understood, also exemplified in the present study because the OS-33 model was excluded from 18 F-FLT-PET analysis due to lack of baseline 18 F-FLT uptake.…”