Ziv-Aflibercept Treatment Reduces Intrahepatic Tumor Growth Of A Preclinical Colorectal Carcinoma Liver Metastasis Model, Monitored Using Non-Invasive Micro-Ultrasound And Bioluminescent Imaging

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 HE 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