title: The use of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kβ/δ inhibitor.
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. (18)F-fluorodeoxyglucose positron emission tomography ((18)F-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 (18)F-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. (18)F-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 (18)F-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 (18)F-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 (18)F-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 (18)F-FDG PET imaging as a sensitive and non-invasive pharmacodynamic biomarker for use in clinical studies with AZD8186.
authors: Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, SK10 4TG, UK. Juliana.maynard@alderleyimaging.com.
authors: Juliana
authors: J
authors: Maynard
authors: Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Sally-Ann
authors: SA
authors: Emmas
authors: Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Francois-Xavier
authors: FX
authors: Blé
authors: Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Hervé
authors: H
authors: Barjat
authors: Drug Safety and Metabolism IMED, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Emily
authors: E
authors: Lawrie
authors: Oncology IMED, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Urs
authors: U
authors: Hancox
authors: Oncology IMED, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Deborah
authors: D
authors: Oakes
authors: Oncology IMED, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Urszula M
authors: UM
authors: Polanska
authors: Oncology IMED, AstraZeneca, Alderley Park, SK10 4TG, UK.
authors: Simon T
authors: ST
authors: Barry