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

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

doi:10.1186/s13550-016-0220-9

Abstract

BackgroundThe 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.ResultsResults 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0220-9) contains supplementary material, which is available to authorized users.

Highlights

The phosphatidylinositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and a promising therapeutic target
AZD8186 inhibits growth of PTEN-null but not PIK3CA/ PI3Kα mutant tumour xenografts Consistent with the hypothesis that PI3Kβ has an important role in promoting the growth of PTEN-null tumours, AZD8186 inhibited the growth of the PTENnull tumour xenograft models 786-0 and U87-MG, but did not inhibit the PIK3CA/ PI3Kα mutant breast tumour xenograft model BT474C (Fig. 1a–c)
In the U87-MG model, a 31 % decrease (p = 0.0004) in 18F-FDG uptake was observed in the AZD8186-treated group compared to vehicle (Fig. 2)

Summary

Introduction

The phosphatidylinositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and a promising therapeutic target. 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. We assessed if 18F-FDG PET could be used as a pharmacodynamic marker to monitor PI3Kβ inhibition by AZD8186, and have potential as a clinical biomarker of PI3Kβ pathway activation, and for patient selection. The phosphatidyl inositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer and is considered a promising therapeutic target to control tumour growth [1]. PIP3 is required for the activation of the serine threonine kinase, AKT, triggering critical pathways involved in metabolism, cell growth, proliferation, motility and survival [4]

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