Measurement of tumor VEGF-A levels with 89Zr-bevacizumab PET as an early biomarker for the antiangiogenic effect of everolimus treatment in an ovarian cancer xenograft model
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue la faisabilité de la tomographie par émission de positrons à l'aide de 89Zr-bevacizumab pour mesurer les niveaux tumoraux de VEGF-A et suivre la réponse à l'évérolimus, un traitement anti-angiogénique, dans les cancers de l'ovaire
Purpose: The mammalian target of rapamycin (mTOR) pathway is frequently activated in ovarian cancers. mTOR inhibitors, like everolimus, can reduce vascular endothelial growth factor-A (VEGF-A) production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with 89Zr-bevacizumab. Experimental design: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780luc+ ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were performed before and after treatment. Ex vivo 89Zr-bevacizumab biodistribution and correlative tissue analyses were performed. 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 89Zr-bevacizumab tumor uptake by 21.7 ± 4.0% (SUVmean 2.3 ± 0.2 versus 2.9 ± 0.2, P < 0.01). Ex vivo biodistribution also demonstrated lower tracer uptake in the tumors of treated compared to control animals (7.8 ± 0.8 %ID/g versus 14.0 ± 1.7 %ID/g, P < 0.01), while 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. 89Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy.
Clinical Cancer Research , résumé, 2012