Abstract
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 (89)Zr-bevacizumab. 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 (89)Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo (89)Zr-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. Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered (89)Zr-bevacizumab tumor uptake by 21.7% ± 4.0% [mean standardized uptake value (SUV(mean)) 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). Tumor VEGF-A levels are decreased by everolimus. (89)Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy.
Highlights
Patients with ovarian cancer often present with advanced stage disease and develop resistance to conventional chemotherapy during the course of treatment, resulting in a poor 30% 5-year survival rate [1]
Tumor VEGF-A levels are decreased by everolimus. 89Zr-bevacizumab positron emission tomography (PET) could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy
The aim of this study was to analyze the effect of everolimus on ovarian cancer VEGF-A secretion in vitro and in vivo, and the potential of serially measuring tumor VEGF-A levels with 89Zr-bevacizumab PET as an early predictive biomarker for everolimus antiangiogenic efficacy in an ovarian cancer xenograft model
Summary
Patients with ovarian cancer often present with advanced stage disease and develop resistance to conventional (platinum-based) chemotherapy during the course of treatment, resulting in a poor 30% 5-year survival rate [1]. Authors' Affiliations: Departments of 1Medical Oncology, 2Gynecological Oncology, 3Hospital and Clinical Pharmacy, and 4Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Because ovarian cancers are often extensively vascularized and overexpress proangiogenic factors, such as VEGF-A, angiogenesis inhibition has been studied as a therapeutic strategy. Phase II and III trials with the VEGF-A–neutralizing antibody bevacizumab or with VEGF receptor (VEGFR)–targeted tyrosine kinase inhibitors (TKI) targeting vascular endothelial cells have shown antitumor activity in a subgroup of patients [2, 3]
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