Measurement of Tumor VEGF-A Levels with Zr-89-Bevacizumab PET as an Early Biomarker for the Antiangiogenic Effect of Everolimus Treatment in an Ovarian Cancer Xenograft Model

Purpose: The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with Zr-89-bevacizumab.

Experimental Design: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780(luc+) ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer Zr-89-labeled bevacizumab were conducted before and after treatment. Ex vivo Zr-89-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry.

Results: Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered Zr-89-bevacizumab tumor uptake by 21.7% +/- 4.0% [mean standardized uptake value (SUVmean) 2.3 +/- 0.2 vs. 2.9 +/- 0.2, P <0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 +/- 0.8% ID/g vs. 14.0 +/- 1.7% ID/g, P <0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P <0.01).

Conclusion: Tumor VEGF-A levels are decreased by everolimus. Zr-89-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy. Clin Cancer Res; 18(22); 6306-14. (C)2012 AACR.