title: Early detection of pemetrexed-induced inhibition of thymidylate synthase in non-small cell lung cancer with FLT-PET imaging.
abstract: Inhibition of thymidylate synthase (TS) results in a transient "flare" in DNA thymidine salvage pathway activity measurable with FLT ([18F]thymidine)-positron emission tomography (PET). Here we characterize this imaging strategy for potential clinical translation in non-small cell lung cancer (NSCLC). Since pemetrexed acts by inhibiting TS, we defined the kinetics of increases in thymidine salvage pathway mediated by TS inhibition following treatment with pemetrexed in vitro. Next, using a mouse model of NSCLC, we validated the kinetics of the pemetrexed-mediated "flare" in thymidine salvage pathway activity in vivo using FLT-PET imaging. Finally, we translated our findings into a proof-of-principle clinical trial of FLT-PET in a human NSCLC patient. In NSCLC cells in vitro, we identified a burst in pemetrexed-mediated thymidine salvage pathway activity, assessed by 3H-thymidine assays, thymidine kinase 1 (TK1) expression, and equilibrative nucleoside transporter 1 (ENT1) mobilization to the cell membrane, that peaked at 2hrs. This 2hr time-point was also optimal for FLT-PET imaging of pemetrexed-mediated TS inhibition in murine xenograft tumors and was demonstrated to be feasible in a NSCLC patient. FLT-PET imaging of pemetrexed-induced TS inhibition is optimal at 2hrs from therapy start; this timing is feasible in human clinical trials.
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.|Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Yizeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Berger
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Urooj
authors.initials: U
authors.lastname: Khalid
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Farwell
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Langer
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Aggarwal
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.affiliation: Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Sharyn I
authors.initials: SI
authors.lastname: Katz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000068437:Pemetrexed / Q000494:pharmacology* / Q000627:therapeutic use; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D013936:Thymidine; D013937:Thymidine Kinase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D033721:Equilibrative Nucleoside Transporter 1; D019275:Radiopharmaceuticals; D000068437:Pemetrexed; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine
keywords: FLT; PET; flare; lung cancer; pemetrexed