The use of 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) as a pathway specific biomarker with AZD8186; a PI3Kβ/δ inhibitor.

504 Objectives The phosphatidyl inositol 3 kinase (PI3K) signalling pathway is frequently altered in human cancer. Activation is controlled by PTEN a tumour suppressor gene. AZD8186 is a PI3Kβ/δ inhibitor, targeting PTEN deficient tumours dependant on deregulated PI3Kβ signalling. It is hypothesised that patients with a dependence on PI3Kβ driven by a PTEN deficiency would benefit from AZD8186 therapy. In addition, targeting more than one protein within the PI3K pathway via combination therapy may give greater efficacy than single agents alone. 18F-FDG PET is often used as a biomarker with inhibitors targeting the PI3K axis because of the association of this pathway with glucose metabolism. The aim of our studies was to evaluate if 18F-FDG PET could be used as a biomarker for AZD8186 and understand effects on combining AZD8186 with AZD2014 (a dual inhibitor of mTORC1/mTORC2) on 18F-FDG-PET uptake. Methods 18F-FDG PET scans were performed in the 786-0 (PI3Kβ-driven cell line) or BT474C (PI3Kα-driven cell line) xenograft models. AZD8186 and/or AZD2014 were administered 2 hours prior to imaging. Results Results showed that 18F-FDG PET is a pathway specific biomarker with AZD8186 giving a significant reduction in 18F-FDG uptake in the PI3Kβ cell line (26.4%) and no change in the PI3Kα cell line (7% increase) supporting the personalised healthcare hypothesis for the project.18F-FDG PET modulation was also tumour specific which is in contrast with other PI3K inhibitors where global changes in 18F-FDG uptake have been demonstrated. Comprehensive pathway inhibition was also observed when compounds were dosed in combination. Tumour 18F-FDG uptake was 42.8% lower when compounds were dosed in combination compared to 25.2% and 25.5% lower when dosed with AZD8186 and AZD2014 alone. Conclusions We showed that 18F-FDG PET is a pathway specific biomarker for AZD8186. It is hypothesised that 18F-FDG-PET could be valuable in understanding the optimum schedule of combination strategies and more over may be able to identify tumours that are specifically dependant on the PI3Kβ isoform.