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.

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 (89)Zr-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 (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. RESULTS: 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). CONCLUSION: 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.

Multiple VEGF family members are simultaneously expressed in ovarian cancer: a proposed model for bevacizumab resistance.

OBJECTIVE: Insight into the expression of multiple vascular endothelial growth factor (VEGF) family members can support the implementation of anti-angiogenic therapy. This study aimed to assess VEGF family member expression in ovarian cancers and related omental metastases. METHODS: Tissue microarrays encompassing 270 primary cancers and 112 paired metastases were immunostained for VEGF-A, VEGF-B, VEGF-C and VEGF-D. Staining intensities were categorized as absent, weak, moderate or strong. Expression was related to clinicopathological characteristics and survival. RESULTS: Immunohistochemical positivity (defined as moderate or strong expression) was observed for VEGF-A in 90%, VEGF-B in 4%, VEGF-C in 41% and VEGF-D in 55% of the primary ovarian cancers. VEGF-A expression correlated with VEGF-C and VEGF-D expression (P < 0.01). Simultaneous positivity for VEGF-A and VEGF-C or VEGF-D was observed in 38% and 54% of the cancers, respectively. Metastases showed positivity for VEGF-A in 78%, VEGF-B in 5%, VEGF-C in 26% and VEGF-D in 45% of cases. VEGF family member expression showed no independent prognostic significance in multivariate survival analysis. CONCLUSION: VEGF-A, VEGF-C and VEGF-D are widely and often simultaneously expressed in ovarian cancer, which may contribute to bevacizumab resistance. Measuring their expression could support a rational, individualized choice of anti-angiogenic therapy and might be of predictive value. Studies are warranted to determine whether combinatorial analysis of VEGF family member expression can be used to predict anti-angiogenic drug efficacy.

Turning promise into progress for antiangiogenic agents in epithelial ovarian cancer.

Despite efforts to improve chemotherapeutic efficacy in epithelial ovarian cancer, outcome for patients with advanced disease has remained unchanged since the introduction of standard carboplatin and paclitaxel. Interest has therefore shifted toward molecularly targeted therapies that interfere with important features of ovarian carcinogenesis, such as angiogenesis. Several angiogenesis inhibitors, targeting vascular endothelial growth factor (VEGF) ligands (bevacizumab, VEGF-Trap) or their receptors (VEGFR-targeted tyrosine kinase inhibitors) have been clinically evaluated. These agents demonstrated efficacy in phase II clinical trials. Results from phase III trials, in which bevacizumab was added to standard frontline chemotherapy, show a modest effect. Although the initial expectations for angiogenesis inhibitors have been tempered, further research is warranted to define their precise place in the treatment of ovarian cancer. This review summarizes the performed and ongoing studies with regard to angiogenesis inhibitors in ovarian cancer, and the available data on biomarkers for response prediction. Preclinical studies evaluating alternative angiogenesis inhibitors will also be discussed.