Effect Of Igf-1r Inhibitor Bms-754807 On Tumor Glucose Metabolism And Proliferation In Sal-Igf Xenografts By Fdg And Flt-Pet Imaging

e14501 Background: The type 1 insulin-like growth factor receptor (IGF-1R) plays a critical role in mitogenesis and survival in a variety of human tumor cells. IGF-1R is also closely related to the insulin receptor (IR). It is becoming increasingly evident that stimulation of IR or IR/IGF-1R hybrid receptors by insulin or IGF-1/2 may contribute to cancer growth, suggesting that both IGF-1R and IR may be targets for cancer therapy. BMS-754807 (‘807) is an oral IGF-1R tyrosine kinase antagonist under development that also blocks IR activity. This study explores the feasibility of fluorodeoxyglucose (FDG) and fluorothymidine (FLT) positron emission tomography (PET) as pharmacodynamic imaging biomarkers in a xenograft model. Methods: Mice were implanted with fragments of Sal-IGF, a transgenic salivary gland tumor expressing constitutively active IGF-1R. Once tumors reached desired size, the mice were divided into 3 treatment groups (vehicle, 6.25 mg/kg ‘807, & 50 mg/kg ‘807 on days 1–4). FDG-PET scans were performed on day -2 (prior to treatment), days 1 & 2 (max/min concentrations post day 1 dose), and days 4 & 5 (max/min day 4 dose). FLT-PET scans were performed on days -2, 2 (min day 1 dose), & 5 (min day 4 dose). Results: With FDG-PET imaging, a 66% reduction (P<0.05, paired t-test) in tumor SUVmean was observed at the end of the 50 mg/kg therapy (day 4) and sustained for 24h (day 5) with a concomitant reduction of 37% in tumor burden by day 5 (P<0.05). FLT-PET studies demonstrated a 45% reduction (P<0.05) in tumor SUVmean observed 24h after the end of 50 mg/kg therapy (day 5) with a concomitant reduction of 50% in tumor burden (day 5, P<0.05). Conclusions: Correlation with tumor growth inhibition suggests feasibility of FDG- PET despite IR blockade. These results support the use of both FDG and FLT PET imaging in clinical trials with ‘807. [Table: see text]