Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033 |
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Authors: | Donna S Dorow Carleen Cullinane Nelly Conus Peter Roselt David Binns Timothy J McCarthy Grant A McArthur Rodney J Hicks |
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Affiliation: | (1) Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia;(2) Pharmacology and Developmental Therapeutics Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia;(3) Translational Research Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre,, Melbourne, Victoria, Australia;(4) Melbourne University Department of Medicine, St. Vincent’s Hospital,, Melbourne, Victoria, Australia;(5) Global Clinical Platforms, Pfizer Global Clinical Technology, Groton, Connecticut, USA |
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Abstract: | Purpose This study was designed as “proof of concept” for a drug development model utilising multi-tracer serial small animal PET
imaging to characterise tumour responses to molecularly targeted therapy.
Methods Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6–8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with 18F]fluorodeoxyglucose, 18F]fluoro-L-thymidine, 18F]fluoro-azoazomycinarabinoside or 18F]fluoromisonidazole. Separate cohorts (n=3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia.
Results During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast,
tracer uptake into CI-1033-treated tumours decreased by 20–60% during treatment. Expression of the glucose transporter Glut-1
and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared
to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in
control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control
tumours but was severely reduced following 7 days of CI-1033 treatment.
Conclusion CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings
correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small
animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific
cellular processes involved in the therapeutic response.
The first two authors contributed equally to the results presented in this report. |
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Keywords: | Molecular imaging Small animal PET Tumour biology FDG PET Hypoxia |
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