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

摘要

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.