Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin

Objective. The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves alpha 4 beta 1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin alpha 4 beta 1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of alpha 4 beta 1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-alpha 4 beta 1 integrin function-blocking antibody. Methods. Integrin alpha 4 beta 1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-alpha 4 beta 1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines. Results. Treatment of tumor-bearing mice with human-specific alpha 4 beta 1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-alpha 4 beta 1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-alpha 4 beta 1 integrin antibodies resulted in increased cell death and doubling time. Conclusions. Our findings support a role for alpha 4 beta 1 integrin in regulating treatment response to carboplatin, implicating alpha 4 beta 1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease. (C) 2013 Elsevier Inc. All rights reserved.