Medical World News

[Preciouslife1]

http://link.springer.com/article/10.1245%2Fs10434-016-5107-5

Antibody-Mediated Blockade of Phosphatidylserine Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinomas Xenografts
Xiaoyun Cheng , Li Li , Philip E. Thorpe, Adam C. Yopp, Rolf A. Brekken , Xianming Huang


Abstract
Background
Currently, the only FDA-approved systemic therapy for hepatocellular carcinoma (HCC) is the multi-receptor tyrosine kinase inhibitor, sorafenib, which provides only modest clinical benefit. We recently showed that treatment with a phosphatidylserine (PS) targeting agent suppresses tumor growth by targeting tumor vasculature and reactivating antitumor immunity.
Methods
We tested the hypothesis that sorafenib increases PS exposure on tumor vasculature, thereby enhancing the antitumor efficacy of PS targeting. We evaluated the efficacy of combining a PS targeting agent (2aG4) with sorafenib in murine xenograft models of human HCC.
Results
Our results demonstrate that combination of 2aG4 and sorafenib had a superior therapeutic effect over single agent therapy. Mechanistic studies showed that sorafenib significantly increased PS exposure on tumor vasculature; the percentage of PS-positive vessels increased from 19 to 52, 23 to 68, and 30 to 55 % in PLC/PRF/5, C3A, and Huh7 tumors, respectively. Combination therapy significantly decreased tumor microvessel density and the level of M2 macrophages, while increasing the apoptotic index of tumor endothelial cells and the frequency of M1 macrophages. Furthermore, we report the findings of a Phase I clinical study of bavituximab, a chimeric version of 2aG4, combined with sorafenib in HCC patients. The Phase I results demonstrate the appropriate dose of bavituximab to be given with sorafenib in future clinical trials.
Conclusions
Overall, these results strongly support the combination of bavituximab with sorafenib as a promising systemic therapeutic strategy for the treatment for advanced HCC patients.
Xiaoyun Cheng and Li Li have contributed equally to this work.

Rolf Brekken and Xianming Huang are consultants to, have equity interest in, and have a sponsored research agreement with Peregrine Pharmaceuticals Inc.

Electronic supplementary material
The online version of this article (doi:10.?1245/?s10434-016-5107-5) contains supplementary material, which is available to authorized users.