Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases

Maria Pia Morelli, Tina Cascone, Teresa Troiani, Concetta Tuccillo, Roberto Bianco, Nicola Normanno, Marco Romano, Bianca Maria Veneziani, Gabriella Fontanini, S. Gail Eckhardt, Sabino De Pacido, Giampaolo Tortora, Fortunato Ciardiello

Research output: Contribution to journalArticle

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Abstract

Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the anti-tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells. Experimental Design: The anti-tumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: The combination of ZD6474 and cetuximab determined synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) xenografts and treated with ZD6474 and/or cetuximab for 4 weeks, a reversible tumor growth inhibition was caused by each drug. In contrast, a more significant tumor growth delay resulted from the combination of the two agents with an approximately 100-110 days increase in mice median overall survival as compared to single agent treatment. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy.

Original languageEnglish
Pages (from-to)344-353
Number of pages10
JournalJournal of Cellular Physiology
Volume208
Issue number2
DOIs
Publication statusPublished - Aug 2006

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Blocking Antibodies
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Tumors
Monoclonal Antibodies
Vascular Endothelial Growth Factor Receptor
Neoplasms
Endothelial cells
Cells
Bearings (structural)
Growth
Cell proliferation
Cell growth
Heterografts
Design of experiments
Endothelial Cells
Vascular Endothelial Growth Factor A
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Cetuximab
Cell Line

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases. / Morelli, Maria Pia; Cascone, Tina; Troiani, Teresa; Tuccillo, Concetta; Bianco, Roberto; Normanno, Nicola; Romano, Marco; Veneziani, Bianca Maria; Fontanini, Gabriella; Eckhardt, S. Gail; De Pacido, Sabino; Tortora, Giampaolo; Ciardiello, Fortunato.

In: Journal of Cellular Physiology, Vol. 208, No. 2, 08.2006, p. 344-353.

Research output: Contribution to journalArticle

Morelli, MP, Cascone, T, Troiani, T, Tuccillo, C, Bianco, R, Normanno, N, Romano, M, Veneziani, BM, Fontanini, G, Eckhardt, SG, De Pacido, S, Tortora, G & Ciardiello, F 2006, 'Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases', Journal of Cellular Physiology, vol. 208, no. 2, pp. 344-353. https://doi.org/10.1002/jcp.20666
Morelli, Maria Pia ; Cascone, Tina ; Troiani, Teresa ; Tuccillo, Concetta ; Bianco, Roberto ; Normanno, Nicola ; Romano, Marco ; Veneziani, Bianca Maria ; Fontanini, Gabriella ; Eckhardt, S. Gail ; De Pacido, Sabino ; Tortora, Giampaolo ; Ciardiello, Fortunato. / Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases. In: Journal of Cellular Physiology. 2006 ; Vol. 208, No. 2. pp. 344-353.
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AU - Cascone, Tina

AU - Troiani, Teresa

AU - Tuccillo, Concetta

AU - Bianco, Roberto

AU - Normanno, Nicola

AU - Romano, Marco

AU - Veneziani, Bianca Maria

AU - Fontanini, Gabriella

AU - Eckhardt, S. Gail

AU - De Pacido, Sabino

AU - Tortora, Giampaolo

AU - Ciardiello, Fortunato

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N2 - Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the anti-tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells. Experimental Design: The anti-tumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: The combination of ZD6474 and cetuximab determined synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) xenografts and treated with ZD6474 and/or cetuximab for 4 weeks, a reversible tumor growth inhibition was caused by each drug. In contrast, a more significant tumor growth delay resulted from the combination of the two agents with an approximately 100-110 days increase in mice median overall survival as compared to single agent treatment. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy.

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