Abstract 5092: Ziv-aflibercept treatment reduces intra-hepatic tumor growth of a preclinical colorectal carcinoma liver metastasis model, monitored using non-invasive micro-ultrasound and bioluminescent imaging.

Abstract

Abstract The liver is a frequent metastatic site for different types of cancers, including colorectal carcinomas (CRC). Therapies that inhibit the angiogenic growth factor VEGF, such as bevacizumab and ziv-aflibercept, are used in combination with chemotherapies to treat metastatic CRC. Ziv-aflibercept (also known as VEGF Trap) is being developed as a part of a collaboration between Sanofi and Regeneron Pharmaceuticals, Inc. and was recently approved by the FDA in metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. To better understand the role of VEGF in metastatic CRC, we aimed to assess the effects of ziv-aflibercept on intrahepatic CRC tumor growth, invasion and angiogenesis in a preclinical model. For that we developed and characterized a CRC liver metastasis model that would allow us to longitudinally assess the effects of ziv-aflibercept on CRC growth in the liver parenchyma using non-invasive high frequency micro-ultrasound and bioluminescent imaging modalities. Briefly, luciferase-expressing HCT116 (human colorectal carcinoma) tumor cells were implanted into the left liver lobe of male CB17 SCID mice using image-guided micro-ultrasound. Tumor growth was monitored using both micro-ultrasound and bioluminescent imaging. When tumors were established (approximately 70 mm3), mice were treated with either control protein (hFc, 25 mg/kg, 2x/wk) or ziv-aflibercept (25 mg/kg, 2x/wk) for up to 13 days. Ziv-aflibercept treatment inhibited tumor growth by 95% compared to control treatment. This inhibition of tumor growth was accompanied by significantly decreased cell proliferation (50-70%), as measured by Ki67 immunohistochemistry, and markedly decreased vessel density (approximately 50%), as revealed by CD31 immunohistochemistry. Ziv-aflibercept did not seem to increase tumor invasiveness, as H&E histology did not reveal dramatic differences at the tumor/stroma border between the ziv-aflibercept and control treated tumors. These experiments confirm that ziv-aflibercept reduces growth and vascularity of colorectal tumors growing in the liver in a preclinical model. Citation Format: Alexander P. Adler, Asma Parveen, Gavin Thurston, Alexandra Eichten. Ziv-aflibercept treatment reduces intra-hepatic tumor growth of a preclinical colorectal carcinoma liver metastasis model, monitored using non-invasive micro-ultrasound and bioluminescent imaging. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5092. doi:10.1158/1538-7445.AM2013-5092