Abstract 4374: Combination of Bevacizumab and oncolytic virus hRr3 in an experimentalmodel of pancreatic carcinoma
Authors: Sahin Tevfik Tolga , Kasuya Hideki , Kanzaki Akiyuki , Gewen Tan , Yamamura Kazuo , Fujii Tsutomu , Takeda Shin , Sugimoto Hiroyuki , Kodera Yasuhiro , Nakao Akimasa 
Published: August 2012

Abstract
Aim: Proangiogenic growth factors stimulate endothelial cells in nearby vessels to proliferate and migrate into the tumor. Vascular endothelial growth factor (VEGF) is an endothelial cell specific growth factor that is known to facilitate angiogenesis. Excess levels of VEGF are linked with poor prognosis. The effect oncolytic herpes viruses (OHSV) on VEGF A are not accurately determined. Nevertheless; limited number of studies on wild type herpes simplex type 1 (HSV1) have been shown to enhance VEGF A. The aim of the present study was to evaluate the effect of combination of OHSV hrR3 with a novel monoclonal VEGF A antibody Bevacizumab in a xenograft experimental model. Materials and Methods: Several cell were tested for expression of VEGFA. BxPC3 cell line had the highest and MIA PaCa-2 had the lowest expression of VEGFA among the other cell lines. 20 BALB-C nu/nu mice were divided into 4 experimental groups. All animals were implanted 5 mm diameter of BxPC-3 tumor xenograft on each side of their flank. After 2 week of observation; Control group (n=5) received no therapy; oncolytic viral therapy group (OVT) (n=5) received 5x106 pfu hrR3 injected intratumorally per week for two weeks; Bevacizumab treated group (BVT) (n=5) received 5mg/kg Bevacizumab intraperitoneally two times a week for 3 weeks; Combination therapy group (CT) (n=5) received both Bevacizumab and hRr3 virus injected intratumorally the same periods as other groups. The same was performed for MIA PaCa-2 cell lines as In order to confirm our results in a low expression cell line. Tumor diameters were evaluated every 3 days by caliper for 8 weeks. Tumor specimen was collected for conventional hematoxylin eosin stain, immunohistochemistochistry for VEGFA, Thrombospondin1, CD 31, HSV type 1 antigen and TUNEL. In MIA PaCa-2 cell line; VEGFA antigen distribution was especially evaluated on day 1, 3, 5, 7, 14 following hRr3 treatment. Results: The BxPC3 tumor volumes of the animals in the combination therapy were significantly lower than the other groups (p&lt;0.05). Nevertheless; we were unable to show a statistically significant difference among OVT and BVT groups in terms of tumor volume. Histopathologically the CT and the OVT group had degenerated cells and low cellular density and expressed HSV antigen. Interestingly we found highest VEGFA expression in OVT group when compared to other groups (p&lt;0.001). Tumor response was highest in combination group in the MIA PaCa-2 tumors as well (p&lt;0.05). In Mia PACA2 tumors VEGFA expression was increasingly expressed starting from day 5 (p&lt;0.05). Conclusion: Oncolytic virus seems to induce the VEGFA and this may be the proangiogenic stimulus in OHSV to induce angiogenesis. If a combination therapy towards blocking the VEGF A can be administered with OHSV; it may enhance the effect of the virus. Combination of OHSV with an antiangiogenic agent such as Bevacizumab seems to be a safe and effective treatment modality.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4374. doi:1538-7445.AM2012-4374