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  • Expression of αV-Integrins in Uterine Serous Papillary Carcinomas; Implications for Targeted Therapy With Intetumumab (CNTO 95), a Fully Human Antagonist Anti-αV-Integrin Antibody

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Uterine Cancer
Expression of αV-Integrins in Uterine Serous Papillary Carcinomas; Implications for Targeted Therapy With Intetumumab (CNTO 95), a Fully Human Antagonist Anti-αV-Integrin Antibody
  1. Marta Bellone, MS*,
  2. Emiliano Cocco, PhD*,
  3. Joyce Varughese, MD*,
  4. Stefania Bellone, PhD*,
  5. Paola Todeschini, MS*,
  6. Karim El-Sahwi, MD*,
  7. Luisa Carrara, MD†,
  8. Federica Guzzo, MD*,
  9. Peter E. Schwartz, MD*,
  10. Thomas J. Rutherford, MD, PhD*,
  11. Sergio Pecorelli, MD†,
  12. Deborah J. Marshall, PhD‡ and
  13. Alessandro D. Santin, MD*
  1. *Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT;
  2. †Division of Gynecologic Oncology, University of Brescia, Brescia, Italy; and
  3. ‡Ortho Biotech Oncology Research and Development, Radnor, PA.
  1. Address correspondence and reprint requests to Alessandro D. Santin, MD, Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Rm 305 LSOG, 333 Cedar St; PO Box 208063, New Haven, CT 06520-8063. E-mail: alessandro.santin{at}yale.edu.

Abstract

Objective: Uterine serous papillary carcinoma (USPC) is an aggressive variant of endometrial cancer characterized by an innate resistance to chemotherapy and poor prognosis. In this study, we evaluated the expression of αV-integrins in primary USPC cell lines and the in vitro ability of intetumumab (CNTO 95), a fully human monoclonal antibody against αV-integrins, to inhibit USPC cell adhesion and migration.

Materials and Methods: The surface expression of integrins belonging to the αV-family, including αVβ3, αVβ5, and αVβ6, was evaluated in 6 primary USPC cell lines using flow cytometry analysis. To test the ability of intetumumab to inhibit USPC cell adhesion and migration, adhesion assays in the presence of vitronectin and migration assays through an 8.0-μm pore polycarbonate membrane also were performed.

Results: We found high expression of the αV-subunit on the cell surface of all 6 primary USPC cell lines tested (100% positive cells; mean fluorescence intensity range, 13.1-39.5). When the expression of single heterodimeric integrins was evaluated, αVβ3, αVβ5, and αVβ6 were expressed on 37.5%, 32.0%, and 16.3% of cells (mean fluorescence intensity range, 6.5-16.2, 9.2-32.5, and 6.2-11.5, respectively). Importantly, in functional assays, low doses of intetumumab were effective in inhibiting adhesion (0.15 μg/mL, P = 0.003) and migration (1.25 μg/mL P = 0.02) of primary USPC cell lines.

Conclusions: The αV-integrins are overexpressed on the cell surface of primary USPC cell lines. Intetumumab may significantly inhibit USPC cell adhesion and migration pathways and may therefore represent a novel treatment option for patients harboring this rare but highly aggressive variant of endometrial cancer.

  • Uterine serous papillary carcinoma
  • CNTO 95
  • Intetumumab
  • αV-integrin

https://doi.org/10.1097/IGC.0b013e3182187324

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    Footnotes

    • This study was supported in part by grants from the Angelo Nocivelli, the Berlucchi, and the Camillo Golgi Foundation, Brescia, Italy, NIH R01 CA122728-01A2 to AS, and grants 501/A3/3 and 0027557 from the Italian Institute of Health (to A.D.S.). This investigation also was supported by NIH Research Grant CA-16359 from the National Cancer Institute.