Abstract 4233: Early detection of pemetrexed-induced inhibition of thymidylate synthase in non-small lung cancer with FLT-PET imaging

Abstract

Abstract Introduction: Successful inhibition of thymidylate synthase (TS) can be imaged with FLT ([18F]thymidine)-positron emission tomography (PET) thereby providing a measure of therapy response on day 1 of therapy. Here we characterize this imaging strategy for implementation into 1st line therapy with pemetrexed and cisplatin for NSCLC. Materials and Methods: The kinetics of pemetrexed-mediated TS inhibition mediated DNA salvage pathway “flare” in DNA was first characterized in vitro using 3H-thymidine DNA incorporation assays, analysis of TK1 protein expression and mobilization of the equilibrative nucleoside transporter 1 to the cell surface membrane. Kinetics of the pemetrexed-mediated “flare” in the salvage pathway was then confirmed in an in vivo mouse model of NSCLC. Finally, a proof-of-principle clinical trial was performed to demonstrate feasibility of imaging of pemetrexed-mediated TS inhibition in human subjects with NSLC. Results: In vitro examination of pemetrexed-induced changes in the salvage pathway revealed a burst in DNA activity that peaked at 2 hrs following the administration of pemetrexed. The addition of cisplatin did not impact the amplitude or timing of the pemetrexed-induced “flare” in the salvage pathway. In vivo imaging of TS inhibition with FLT-PET confirmed a peak in salvage pathway activity at 2 hrs. Imaging of pemetrexed-induced TS inhibition in a human clinical trial demonstrated feasibility with imaging at the 2 hr time point. Conclusion: FLT-PET measured efficacy of pemetrexed-induced TS inhibition is optimal at 2 hrs from the start of therapy. This timing of FLT-PET imaging is feasible in human clinical trials. Citation Format: Xiao Chen, Ian Berger, Urooj Khalid, Jenny Cai, Akash Patel, Sharyn I. Katz. Early detection of pemetrexed-induced inhibition of thymidylate synthase in non-small lung cancer with FLT-PET imaging. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4233.