Biomarkers for antitumor activity of bevacizumab in gastric cancer models

Abstract

BackgroundBevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer, because VEGF has been reported to be involved in the development of gastric cancer as well as other cancers. On the other hand, there are no established biomarkers to predict the bevacizumab efficacy in spite of clinical needs. Therefore, we tried to identify the predictive markers for efficacy of bevacizumab in gastric cancer patients by using bevacizumab-sensitive and insensitive tumor models.MethodsNine human gastric and two colorectal cancer mouse xenografts were examined for their sensitivity to bevacizumab. We examined expression levels of angiogenic factors by ELISA, bioactivity of VEGF by phosphorylation of VEGFR2 in HUVEC after addition of tumor homogenate, tumor microvessel density by CD31-immunostaining, and polymorphisms of the VEGF gene by HybriProbe™ assay.ResultsOf the 9 human gastric cancer xenograft models used, GXF97, MKN-45, MKN-28, 4-1ST, SC-08-JCK, and SC-09-JCK were bevacizumab-sensitive, whereas SCH, SC-10-JCK, and NCI-N87 were insensitive. The sensitivity of the gastric cancer model to bevacizumab was not related to histological type or HER2 status. All tumors with high levels of VEGF were bevacizumab-sensitive except for one, SC-10-JCK, which had high levels of VEGF. The reason for the refractoriness was non-bioactivity on the phosphorylation of VEGFR2 and micro-vessel formation of VEGF, but was not explained by the VEGF allele or VEGF165b. We also examined the expression levels of other angiogenic factors in the 11 gastrointestinal tumor tissues. In the refractory models including SC-10-JCK, tumor levels of another angiogenic factor, bFGF, were relatively high. The VEGF/bFGF ratio correlated more closely with sensitivity to bevacizumab than with the VEGF level.ConclusionsVEGF levels and VEGF/bFGF ratios in tumors were related to bevacizumab sensitivity of the xenografts tested. Further clinical investigation into useful predictive markers for bevacizumab sensitivity is warranted.

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

“…Both parameters were even more inhibited when E4031 was added in combination with the VEGF-A antibody (bevacizumab; ref. 31), with a schedule that was able to maintain tumor inhibition even after treatment suspension. Therefore, the blocking of hERG1 through noncardiotoxic blockers (either existing, as in ref.…”

Surgery after Preoperative Chemotherapy for Patients with Unresectable Advanced Gastric Cancer

“…In addition, preoperative chemotherapy may have some advantages, such as the delivery of antitumor agents being more efficient if administered before surgical disruption of the vasculature and that tumor downstaging may increase the success rate of complete surgical resection. To improve the prognosis of non-curative gastric cancer, combined preoperative targeting chemotherapy (DCS and anti-targeting agents) [30,31] should be administered rather than postoperative combination chemotherapy using docetaxel with S-1, CDDP with S-1 or S-1 alone [27,29,32]. …”

Promising Targeted Therapies Genes and Prognostic Biomarkers of Gastric Cancer

“…Помимо этого, bFGF способствует пролиферации и миграции клеток. Предполагается, что во время ангиогенеза между bFGF и VEGF возникает перекрестная связь (crosstalk), так как bFGF увеличивает экспрессию NRP1 -корецептора семейства VEGF [17]. Одновременная экспрессия VEGF и bFGF приводит к активному росту опухоли, с высокой плотностью и проходимостью сосудов [18].…”