The use of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kβ/δ inhibitor
| Autor: | Simon T. Barry, François-Xavier Blé, Emily Lawrie, Sally-Ann Emmas, Urs Hancox, Hervé Barjat, Deborah Oakes, Juliana Maynard, Urszula M. Polanska |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty biology medicine.diagnostic_test Kinase business.industry Phases of clinical research medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Positron emission tomography 030220 oncology & carcinogenesis Glioma biology.protein Cancer research Medicine PTEN Biomarker (medicine) Radiology Nuclear Medicine and imaging business Protein kinase B PI3K/AKT/mTOR pathway Original Research |
| Zdroj: | EJNMMI Research |
| ISSN: | 2191-219X |
| Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0220-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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