[18F]FDG-PET as a rapid, non-invasive pharmacodynamic (PD) marker of response to IGF1-R/IR targeted therapy in preclinical models

445 Objectives To determine the potential of [18F]FDG-PET as an early pharmacodynamic (PD) biomarker of treatment response to OSI-906, a dual inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) inhibitor in preclinical models. Methods OSI-906 sensitive NCI-H292 and insensitive NCI-H441 human lung carcinoma xenograft tumors were grown subcutaneously in athymic nude mice. For PD studies, [18F]FDG-PET images were collected 2, 4, 8 and 24 hours after a single oral administration of 60 mg/kg OSI-906 or vehicle control. Tumor tissue was collected immediately following PET imaging and used for molecular PD assays measuring target inhibition (phospho-IGF-1R, phospho-IR) and inhibition of downstream signaling (e.g. phospho-AKT). Results [18F]FDG uptake was significantly reduced in NCI-H292 bearing mice at 2, 4, and 24 hours following treatment with a single dose of 60 mg/kg OSI-906 compared to vehicle controls. Reduced uptake of the radiotracer correlated with significant target inhibition of both phospho-IGF1-R and phospho-IR as determined by RTK array analysis. Additionally, Western blot analysis of the tumor lysates confirmed inhibition of phospho-AKT and other markers associated with altered glycolysis. In contrast, in the NCI-H441 tumors, no change in [18F]FDG uptake was detected at any time point. Conclusions [18F]FDG-PET appears to be a promising rapid and non-invasive PD marker for OSI-906 and possibly other inhibitors of this target class. This approach may be valuable in the clinical setting where accurate assessment of PD is often limited by the availability of tumor biopsy specimens. Importantly, choice of proper imaging time points is necessary for optimal determination of these early PD effects