PMID- 28806782 OWN - NLM STAT- MEDLINE DCOM- 20171009 LR - 20191210 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 12 IP - 8 DP - 2017 TI - 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 PI3Kalpha inhibitor. PG - e0183048 LID - 10.1371/journal.pone.0183048 [doi] LID - e0183048 AB - BACKGROUND: 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. AZD8835 is a PI3K inhibitor, with selectivity against PI3K alpha and delta 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. RESULTS: Results 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. CONCLUSIONS: Our 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. FAU - Maynard, Juliana AU - Maynard J AD - Personalised Healthcare & Biomarkers, AstraZeneca, Cheshire, United Kingdom. FAU - Emmas, Sally-Ann AU - Emmas SA AD - Personalised Healthcare & Biomarkers, AstraZeneca, Cheshire, United Kingdom. FAU - Ble, Francois-Xavier AU - Ble FX AD - Personalised Healthcare & Biomarkers, AstraZeneca, Cheshire, United Kingdom. FAU - Barjat, Herve AU - Barjat H AD - Personalised Healthcare & Biomarkers, AstraZeneca, Cheshire, United Kingdom. FAU - Lawrie, Emily AU - Lawrie E AD - Drug Safety and Metabolism iMED, AstraZeneca, Cheshire, United Kingdom. FAU - Hancox, Urs AU - Hancox U AD - Oncology Imed, Astrazenenca, Cheshire, United Kingdom. FAU - Polanska, Urszula M AU - Polanska UM AD - Oncology Imed, Astrazenenca, Cheshire, United Kingdom. FAU - Pritchard, Alison AU - Pritchard A AD - Oncology Imed, Astrazenenca, Cheshire, United Kingdom. FAU - Hudson, Kevin AU - Hudson K AD - Oncology Imed, Astrazenenca, Cheshire, United Kingdom. LA - eng PT - Journal Article DEP - 20170814 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (AZD8835) RN - 0 (Biomarkers, Tumor) RN - 0 (Blood Glucose) RN - 0 (Oxadiazoles) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) SB - IM MH - Animals MH - Biomarkers, Tumor/metabolism MH - Blood Glucose/metabolism MH - Cell Line, Tumor MH - Dose-Response Relationship, Drug MH - Female MH - Fluorodeoxyglucose F18/*metabolism MH - Gene Knockdown Techniques MH - Homeostasis/drug effects MH - Humans MH - Mice, Nude MH - Oxadiazoles/administration & dosage/*pharmacokinetics/*pharmacology MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Phosphoinositide-3 Kinase Inhibitors MH - Piperidines/administration & dosage/*pharmacokinetics/*pharmacology MH - Positron-Emission Tomography/*methods MH - Protein Kinase Inhibitors/administration & dosage/*pharmacokinetics/*pharmacology MH - Signal Transduction/drug effects MH - Xenograft Model Antitumor Assays PMC - PMC5555689 COIS- Competing Interests: All authors are current or former employees and shareholders in AstraZeneca. This does not alter our adherence to PLOS ONE policies on sharing data and materials. EDAT- 2017/08/15 06:00 MHDA- 2017/10/11 06:00 PMCR- 2017/08/14 CRDT- 2017/08/15 06:00 PHST- 2017/05/04 00:00 [received] PHST- 2017/07/30 00:00 [accepted] PHST- 2017/08/15 06:00 [entrez] PHST- 2017/08/15 06:00 [pubmed] PHST- 2017/10/11 06:00 [medline] PHST- 2017/08/14 00:00 [pmc-release] AID - PONE-D-17-17192 [pii] AID - 10.1371/journal.pone.0183048 [doi] PST - epublish SO - PLoS One. 2017 Aug 14;12(8):e0183048. doi: 10.1371/journal.pone.0183048. eCollection 2017.