The use of .sup.18F-Fluoro-deoxy-glucose positron emission tomography

The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K [alpha] and [delta] isoforms...

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Bibliographic Details
Published in:PloS one 2017-08, Vol.12 (8), p.e0183048
Main Authors: Maynard, Juliana, Emmas, Sally-Ann, Ble, Francois-Xavier, Barjat, Herve, Lawrie, Emily, Hancox, Urs, Polanska, Urszula M, Pritchard, Alison, Hudson, Kevin
Format: Article
Language:English
Subjects:
Biological markers
Clinical trials
Glucose
Positron emission tomography
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Summary:The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K [alpha] and [delta] isoforms, which is currently in Phase 1 clinical trials. .sup.18 F-Fluoro-deoxy-glucose positron emission tomography (.sup.18 F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development. It has been used widely with PI3K inhibitors both clinically and pre-clinically because of the role of the PI3K pathway in glucose metabolism. In this study we investigated the potential of .sup.18 F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if .sup.18 F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. .sup.18 F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static .sup.18 F-FDG PET was performed. Treatment groups received AZD8835 by oral gavage at a dose volume of 10ml/kg. Treatment groups received either 3, 6, 12.5, 25 or 50mg/kg AZD8835. Tumour growth was monitored throughout the study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis was performed. Our pre-clinical studies support the use of .sup.18 F-FDG PET imaging as a sensitive and non- invasive pharmacodynamic biomarker (understanding the role of PI3K signalling in glucose uptake) for AZD8835 with a decrease in .sup.18 F-FDG uptake observed at only two hours post treatment. The decrease in .sup.18 F-FDG uptake was dose dependent and data showed excellent PK/PD correlation. This data supports and parallels observations obtained with this class of compounds in patients
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0183048