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Antibody-Mediated Blockade of Phosphatidylserine Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinomas Xenografts

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Acknowledgment

The authors thank Dan Ye and Janie Iglehart for technical assistance and Drs. Marietta Kovacs and Alan Schroit for discussions and comments on the manuscript. This work was initiated under the direction of Dr. Philip Thorpe, who unfortunately passed away suddenly in March 2013. This work was supported by a sponsored research agreement with Peregrine Pharmaceuticals Inc. (Tustin, CA).

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    Authors and Affiliations

    1. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA

      Xiaoyun Cheng PhD, Li Li PhD, Philip E. Thorpe PhD, Rolf A. Brekken PhD & Xianming Huang PhD

    2. Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

      Adam C. Yopp MD & Rolf A. Brekken PhD

    3. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA

      Philip E. Thorpe PhD, Rolf A. Brekken PhD & Xianming Huang PhD

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    1. Xiaoyun Cheng PhD
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    2. Li Li PhD
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    3. Philip E. Thorpe PhD
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    4. Adam C. Yopp MD
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    Corresponding authors

    Correspondence to Rolf A. Brekken PhD or Xianming Huang PhD.

    Additional information

    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.

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    Cheng, X., Li, L., Thorpe, P.E. et al. Antibody-Mediated Blockade of Phosphatidylserine Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinomas Xenografts. Ann Surg Oncol 23 (Suppl 5), 583–591 (2016). https://doi.org/10.1245/s10434-016-5107-5

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    • DOI: https://doi.org/10.1245/s10434-016-5107-5

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