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EJNMMI Research
Published in: EJNMMI Research 1/2016

Open Access 01-12-2016 | Original research

The use of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kβ/δ inhibitor

Authors: Juliana Maynard, Sally-Ann Emmas, Francois-Xavier Blé, Hervé Barjat, Emily Lawrie, Urs Hancox, Deborah Oakes, Urszula M. Polanska, Simon T. Barry

Published in: EJNMMI Research | Issue 1/2016

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Abstract

Background

The phosphatidylinositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and a promising therapeutic target. AZD8186 (AstraZeneca) is a PI3Kβ/δ inhibitor, currently in phase 1 clinical trials. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is often used as a biomarker for inhibitors targeting the PI3K axis because of the association of this pathway with glucose metabolism. In this study, we assessed if 18F-FDG PET could be used as a pharmacodynamic marker to monitor PI3Kβ inhibition by AZD8186, and hence have potential as a clinical biomarker of PI3Kβ pathway activation, and for patient selection. 18F-FDG PET scans were performed in nude mice bearing 786-0 renal, U87-MG glioma, and BT474C breast xenograft models. Mice were fasted prior to imaging and static 18F-FDG PET imaging was performed. Tumour growth was monitored throughout each study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis performed.

Results

Results showed that in PTEN null tumour xenograft models, 786-0 and U87-MG, the PI3Kβ inhibitor AZD8186 reduces 18F-FDG uptake at a dose of 50 mg/kg, the same dose which causes tumour inhibition, while it has no impact in a PI3Kα mutant tumour xenograft BT474C. Consistent with the change in 18F-FDG uptake, AZD8186 also modulated AKT and associated glucose pathway biomarkers in the PTEN null tumour xenografts but not in PTEN wild-type tumours.

Conclusions

Our pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and non-invasive pharmacodynamic biomarker for use in clinical studies with AZD8186.
Appendix
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Metadata
Title
The use of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kβ/δ inhibitor
Authors
Juliana Maynard
Sally-Ann Emmas
Francois-Xavier Blé
Hervé Barjat
Emily Lawrie
Urs Hancox
Deborah Oakes
Urszula M. Polanska
Simon T. Barry
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-016-0220-9

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