F-18-FPPRGD2 and F-18-FDG PET of Response to Abraxane Therapy

Abraxane (nanoparticle albumin-bound paclitaxel) is an anticancer drug approved by the Food and Drug Administration. However, the mechanism of action of Abraxane is complex, and no established biomarker is available to accurately monitor its treatment outcomes. The aim of this study was to investigate whether the integrin-specific PET tracer F-18-FPPRGD2 (investigational new drug 104150) can be used to monitor early response of tumors to Abraxane therapy. Methods: Orthotopic MDA-MB-435 breast cancer mice were treated with Abraxane (25 mg/kg every other day, 3 doses) or phosphate-buffered saline. Tumor volume was monitored by caliper measurement. PET scans were obtained before and at different times after the start of treatment (days 0, 3, 7, 14, and 21) using F-18-FPPRGD2 and F-18-FDG. The tumoricidal effect was also assessed ex vivo by immunohistochemistry. Results: Abraxane treatment inhibited the tumor growth, and a significant difference in tumor volume could be seen at day 5 after the initiation of treatment. The tumor uptake of F-18-FPPRGD2 in the Abraxane-treated group was significantly lower on days 3 and 7 than at baseline but returned to the baseline level at days 14 and 21, indicative of relapse of the tumors after the treatment was halted. Immunohistologic staining confirmed that the change of F-18-FPPRGD2 uptake correlated with the variation of integrin level in the tumor vasculature induced by Abraxane treatment. No significant change of tumor (rather than vascular) integrin expression was observed throughout the study. No significant decrease of F-18-FDG uptake was found between the treated and the control tumors on days 3, 14, and 21, although an increase in F-18-FDG tumor uptake of treated mice, as compared with the control mice, was found on day 7. The increase of F-18-FDG on day 7 was related to the inflammatory response during therapy. Conclusion: Abraxane-mediated downregulation of integrin alpha v beta 3 expression on tumor endothelial cells can be quantitatively visualized by PET. The change of integrin expression precedes that of tumor size. Consequently, F-18-FPPRGD2 PET is superior to F-18-FDG PET in monitoring early response to treatment, favoring its potential clinical translation.