Abstract 5273: Multiplexed PET probes for imaging breast cancer early response to VEGF121/rGel treatment

Abstract

Abstract Purpose: Monitoring of tumor early response to therapy is important in clinical oncology to reduce side effects and save costs, especially with the growing number of alternative treatment regimens that are only effective in select subgroups of patients. VEGF121/rGel fusion protein has been shown to completely suppress ocular neovascularization and inhibit the growth of melanoma and glioblastoma, as well as prostate, breast, and bladder tumor models with low systemic toxicity. The aim of this study was to apply multiplexed positron emission tomography (PET) probes to monitor glucose metabolism, cellular proliferation, tumor hypoxia and angiogenesis during VEGF121/rGel therapy of breast cancer. Methods: Orthotopic MDA-MB-435 breast cancer tumor-bearing mice were treated with 2 doses of VEGF121/rGel at days 1 and 3. Tumor growth was monitored by caliper measurement. During the therapeutic process, longitudinal PET scans were performed using 18F-FDG, 18F-FLT, 18F-FMISO, and 18F-FPPRGD2 as imaging tracers to evaluate tumor glucose metabolism, cellular proliferation, tumor hypoxia, and angiogenesis, respectively. Imaging metrics were validated by immunohistochemical analysis of the corresponding biomarkers. Results: Two doses of 12 mg/kg VEGF121/rGel, administered intraperitoneally, resulted in initial delay of tumor growth, but the growth resumed 4 days after tumor treatment was stopped. VEGF121/rGel treatment led to significantly decreased uptake of 18F-FPPRGD2 at day 1 (24.0 ± 8.8%, p < 0.05) and day 3 (36.3 ± 9.2%, p < 0.01), relative to the baseline, which slowly recovered to the baseline at day 14. 18F-FMISO uptake was increased in the treated tumors at day 1 (23.9 ± 15.7%, p < 0.05) and day 3 (51.4 ± 29.4%, p < 0.01), as compared to the control group. At day 7 and 14, 18F-FMISO uptake restored to the baseline level. The relative reductions in FLT uptake in treated tumors were approximately 13.0 ± 4.5% at day 1 and 25.0 ± 4.4% (p < 0.01) at day 3. No significant change of 18F-FDG uptake was observed in VEGF121/rGel treated tumors, compared with the control group. The imaging findings were supported by ex vivo analysis of related biomarkers. Conclusions: Longitudinal imaging studies with 4 PET tracers demonstrated the feasibility and usefulness of multiplexed probes for quantitative measurement of anti-tumor effects of VEGF121/rGel at the early stage of treatment. 18F-FLT, 18F-FMISO and 18F-FPPRGD2 are superior to 18F-FDG in monitoring therapy response, as supported by ex vivo analyses of related biomarkers. This pre-clinical study should be helpful in accelerating anti-cancer drug development and promoting the clinical translation of molecular imaging in tumor therapy response monitoring. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5273. doi:10.1158/1538-7445.AM2011-5273