title: Antibody-Mediated Blockade of Phosphatidylserine Enhances the Antitumor Effect of Sorafenib in Hepatocellular Carcinomas Xenografts.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Overall, these results strongly support the combination of bavituximab with sorafenib as a promising systemic therapeutic strategy for the treatment for advanced HCC patients.
authors: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Xiaoyun
authors: X
authors: Cheng
authors: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Li
authors: L
authors: Li
authors: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Philip E
authors: PE
authors: Thorpe
authors: Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Adam C
authors: AC
authors: Yopp
authors: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA. rolf.brekken@utsouthwestern.edu.|Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. rolf.brekken@utsouthwestern.edu.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA. rolf.brekken@utsouthwestern.edu.
authors: Rolf A
authors: RA
authors: Brekken
authors: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA. xianming.huang@utsouthwestern.edu.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA. xianming.huang@utsouthwestern.edu.
authors: Xianming
authors: X
authors: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010641:Phenotype; D010671:Phenylurea Compounds / Q000008:administration & dosage; D010718:Phosphatidylserines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069283:Rituximab / Q000494:pharmacology; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D010671:Phenylurea Compounds; D010718:Phosphatidylserines; D009536:Niacinamide; D000069283:Rituximab; D000077157:Sorafenib; C547825:bavituximab