The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor.

Urszula M. Polanska,Matthew Bogyo,Francois-Xavier Ble,Kevin Hudson,Sally-Ann Emmas,Juliana Maynard,Herve Barjat,Alison Pritchard,Emily Lawrie,Urs Hancox

doi:10.1371/journal.pone.0183048

Abstract

BackgroundThe 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 α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-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 18F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if 18F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. 18F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static 18F-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.ResultsResults showed that AZD8835 reduced 18F-FDG uptake at a dose of 12.5, 25 and 50mg/kg with no significant reduction at doses of 3 and 6mg/kg. These results were consistent with other pharmacodynamics biomarkers measured and show 18F-FDG PET as a sensitive biomarker with the ability to determine the minimal effective dose of AZD8835.ConclusionsOur pre-clinical studies support the use of 18F-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 18F-FDG uptake observed at only two hours post treatment. The decrease in 18F-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

Highlights

The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target [1]
Our pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and noninvasive pharmacodynamic biomarker for AZD8835 with a decrease in 18F-FDG uptake observed at only two hours post treatment
No drugs aimed at cancers with PIK3CA mutations have been approved by the FDA to date, several PI3K agents targeting the PIK3CA gene product, targeting PI3Kα, have entered into Phase 1 clinical trials [4] including BYL719 (Novartis) and GDC0032 (Genentech)

Summary

Introduction

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 [1]. GDC-0032 is a selective inhibitor of PI3K with reduced inhibitory activity against PI3Kβ and preferentially inhibits PIK3CA mutant cells relative to cells with wild type PI3K. It has been in clinical trials since 2012 [6]. 18F-Fluoro-deoxyglucose positron emission tomography (18F-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. 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

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