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

Abstract

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 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 (i.p.) for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo89Zr-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 89Zr-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. 89Zr-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. ©2012 AACR.

Everolimus Reduces 89Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

“…We showed that everolimus lowered 89 Zr-bevacizumab uptake in an ovarian cancer xenograft model and coincided with lowered tumor VEGF-A levels (16). Moreover, this approach is feasible in patients.…”

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

“…89 Zr-labeled bevacizumab PET imaging may help in assessment of the inter-and intrapatient heterogeneity of drug biodistribution in vivo, thereby predicting the presence or absence of a response in patients subsequently treated with bevacizumab. Studies in both mice and adult patients confirmed that 89 Zr-bevacizumab PET imaging was feasible and able to reveal bevacizumab accumulation in VEGF-positive tumors (7,(12)(13)(14). In addition, in adult renal cancer tumors, 89 Zr-bevacizumab uptake was correlated with a response to bevacizumab treatment (13).…”

“…These postinjection times were based on previous research in mice and clinical studies in adults with 89 Zr-bevacizumab (7,12,14). The production and purification of 89 Zr and its coupling to bevacizumab were performed in accordance with good manufacturing practice at VU University Medical Center.…”

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

“…VEGF/VEGFR antibodies have been labeled with various radioisotopes for the imaging of VEGFR expression in various disease models (20). For example, extracellular VEGF imaging was accomplished by coupling anti-VEGF monoclonal antibodies (bevacizumab, HuMV833) with 89 Zr (21,22), 111 In (23), and 124 I (24). Recombinant VEGF 165 was efficiently labeled with 123 I and VEGF 121 with both 99m Tc and 64 Cu for VEGF imaging in preclinical models (25)(26)(27)(28).…”