Abstract 3643: Phosphatidylserine-targeting antibody combined with Sorafenib has strong anti-tumor activity against human hepatocellular carcinomas in mice

Abstract

Abstract Hepatocellular Carcinoma (HCC) is the third leading cause of cancer-related deaths in the world. The incidence of the HCC is increasing in the United States. HCC is refractory to most forms of therapy. Sorafenib is the only chemotherapeutic agent approved for the treatment of advanced HCC. Therefore, there is a huge unmet need for a new systemic therapy for HCC patients. A promising approach would be to combine sorafenib with bavituximab to treat HCC. Bavituximab is a vascular targeting antibody that is in Phase IIb clinical trials in patients with non-small cell lung cancer (NSCLC). Bavituximab targets phosphatidylserine (PS), which is normally intracellular but becomes exposed on the external surface of vascular endothelium in tumors. Bavituximab binds to PS-expressing tumor vascular endothelial cells and causes monocytes and macrophages to attack the vessels by antibody-dependent cellular cytotoxicity (ADCC). This results in death of tumor cells through deprivation of oxygen and nutrients. Chemotherapy and irradiation increase the exposure of PS on tumor vessels and enhance the anti-tumor activity of bavituximab-related antibodies in multiple rodent tumor models. We hypothesized that sorafenib would also induce exposure of PS on HCC vasculature because it interferes with anti-apoptotic signaling by VEGF and other angiogenic growth factors. We found that sorafenib induced PS exposure on human microvascular endothelial cells in vitro and in vivo. Treatment of mice bearing subcutaneous C3A, Huh7 or PLC/PRF/5 HCC tumors with sorafenib increased PS exposure on tumor vessels from 21% to 51% in PLC/PRF/5 tumors, from 22% to 67% in C3A tumors, and from 32% to 52% in Huh7 tumors. Combining a murine version of bavituximab with sorafenib significantly improved the anti-tumor effect in the PLC/PRF/5 xenograft model. The combination inhibited tumor growth by 95%, as compared with 80% for sorafenib alone (p<0.05). Bavituximab in combination with sorafenib has promise as a new systemic therapy for the treatment of advanced HCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3643. doi:10.1158/1538-7445.AM2011-3643