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Aim. Tyrosine kinase inhibitors belong to a promising class of cancer therapeutics. BMS-690514, an inhibitor of the HER1, HER2 and HER4 tyrosine kinases, also exhibits VEGFR2 tyrosine kinase inhibition. The aim of this work is to evaluate the efficacy of BMS-690514 using tumor glucose metabolism measured by FDG-PET imaging in tumor xenographs.

Methods. Five million L2987 lung carcinoma tumor cells were implanted in each of 29 female, athymic nude mice (21.9 ± 2.2 g). The tumors were allowed to grow until 381 ± 255 mg at the start of the experiment. The animals were sorted into 2 groups. The mice in Group A was treated with 90 mg/kg doses of BMS-690514 (n=14) for 14 days. Group B was an untreated control group (n=15). FDG-PET images were acquired using a Focus 120 microPET at the baseline prior to the start of treatment and after 14 day drug treatment on day 15. A subset of animals from Groups A (n=6) were FDG-PET imaged 8 days after the end of chemotherapy treatment. The standardized uptake values (SUV) for the tumor were calculated from volumes of interest (obtained from ROIs) placed on the reconstructed images.

Results. The average FDG uptake in Group A (BMS-690514, 90mpk) was reduced by 29% over the two week period (p<0.05), while the average tumor size grew by 72% (p<0.05). In Group B (control), average FDG uptake was increased by 12%, while the average tumor size grew by 184% (p<0.05). Prior to treatment, the average FDG uptake in dosed group was not statistically different from control. After 14 days of treatment, the average FDG uptake in the dosed group became statistically different from the control group. One week after the end of chemotherapy treatment, the average FDG uptake in the subset of animals in Group A (BMS-690514 treated) increased by 70% (p<0.05), while the average tumor size grew by 74% (p<0.05).

Conclusions. The significant reduction in FDG uptake of the BMS-690514 dosed group indicates that BMS-690514 is effective in reducing the tumor metabolism. Although the FDG uptake was reduced while the tumor size grew after 14 days of dosing, the tumor cytostasis 8 days after the end of treatment (Day 22) may indicate that BMS-690514 is more efficient in delaying the tumor growth in a sustained manner even after discontinuation of dosing. This is consistent with DCE MRI data that BMS-690514 is efficient in reducing the tumor microcirculation in mice treated with three doses within 48 hours.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA