Non-invasive imaging of Mitogenic Extracellular Kinase inhibition by PD0325901
Year: 2008
Session type: Poster / e-Poster / Silent Theatre session
1Imperial College London, London, UK, 2Wolfson Brain Imaging Center, Cambridge, UK, 3Huddinge University Hospital, Stockholm, Sweden, 4Institute of Cancer Research Institute, Sutton, Surrey, UK
Abstract
The mitogenic extracellular kinase1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cell types in vitro. In SKMEL-28 cells (with an endogenous activating V600E BRAF mutation), the drug rapidly decreased phosphorylated ERK1/2, cyclin D1 and thymidine kinase 1 (TK1) protein levels.
We investigated if 3’-deoxy-3’-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET) imaging could be used as an early pharmacodynamic read-out of drug-induced growth inhibition in vivo. SKMEL-28 and HCT116 (with endogenous activating mutation in KRAS) tumor-bearing mice treated daily with PD0325901 at 25 mg/kg were imaged by dynamic [18F]FLT-PET after 1 and 10 days of initiating treatment. The drug rapidly decreased [18F]FLT uptake after 1 day of treatment, and this effect was maintained after 10 days of treatment. The normalized uptake of [18F]FLT (at 60 min; NUV60) in SKMEL-28 xenografts after 1 day of vehicle or PD0325901 was 1.52±0.32 versus 0.72±0.26, respectively (P = 0.03). In this model, NUV60 after 10 days was 1.38±0.26 versus 0.93±0.1, respectively (P = 0.03). The corresponding values for HCT116 tumors were 1.70±0.35 versus 0.93±0.19 (P = 0.03) after 1 day, and 1.73±0.08 versus 0.91±0.1 (P = 0.03) after 10 days. Similar changes were found for other [18F]FLT retention parameters. The changes in [18F]FLT-PET occurred in parallel with changes in phosphorylated ERK1/2, cyclin D1, TK1 protein and Ki67 labeling index.
In summary, [18F]FLT-PET is a promising early pharmacodynamic marker of MEK1/2 inhibition in tumors with or without mutation in the BRAF gene.
Acknowledgments
This work was supported by Cancer Research UK.
The mitogenic extracellular kinase1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cell types in vitro. In SKMEL-28 cells (with an endogenous activating V600E BRAF mutation), the drug rapidly decreased phosphorylated ERK1/2, cyclin D1 and thymidine kinase 1 (TK1) protein levels.
We investigated if 3’-deoxy-3’-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET) imaging could be used as an early pharmacodynamic read-out of drug-induced growth inhibition in vivo. SKMEL-28 and HCT116 (with endogenous activating mutation in KRAS) tumor-bearing mice treated daily with PD0325901 at 25 mg/kg were imaged by dynamic [18F]FLT-PET after 1 and 10 days of initiating treatment. The drug rapidly decreased [18F]FLT uptake after 1 day of treatment, and this effect was maintained after 10 days of treatment. The normalized uptake of [18F]FLT (at 60 min; NUV60) in SKMEL-28 xenografts after 1 day of vehicle or PD0325901 was 1.52±0.32 versus 0.72±0.26, respectively (P = 0.03). In this model, NUV60 after 10 days was 1.38±0.26 versus 0.93±0.1, respectively (P = 0.03). The corresponding values for HCT116 tumors were 1.70±0.35 versus 0.93±0.19 (P = 0.03) after 1 day, and 1.73±0.08 versus 0.91±0.1 (P = 0.03) after 10 days. Similar changes were found for other [18F]FLT retention parameters. The changes in [18F]FLT-PET occurred in parallel with changes in phosphorylated ERK1/2, cyclin D1, TK1 protein and Ki67 labeling index.
In summary, [18F]FLT-PET is a promising early pharmacodynamic marker of MEK1/2 inhibition in tumors with or without mutation in the BRAF gene.
Acknowledgments
This work was supported by Cancer Research UK.
