Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model

Maria K. Gule, Yunyun Chen, Daisuke Sano, Mitchell J. Frederick, Ge Zhou, Mei Zhao, Zvonimir L. Milas, Chad E. Galer, Ying C. Henderson, Samar A. Jasser, David L. Schwartz, James A. Bankson, Jeffrey N. Myers, Stephen Y. Lai

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Abstract

Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear. Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature. Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control. Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

Original languageEnglish (US)
Pages (from-to)2281-2291
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2011

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Vascular Endothelial Growth Factor Receptor
Epidermal Growth Factor Receptor
Growth
Neoplasms
Heterografts
Cell Line
Therapeutics
Blood Vessels
Capillary Permeability
Anaplastic Thyroid Carcinoma
Microsatellite Repeats
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Research Design
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model. / Gule, Maria K.; Chen, Yunyun; Sano, Daisuke; Frederick, Mitchell J.; Zhou, Ge; Zhao, Mei; Milas, Zvonimir L.; Galer, Chad E.; Henderson, Ying C.; Jasser, Samar A.; Schwartz, David L.; Bankson, James A.; Myers, Jeffrey N.; Lai, Stephen Y.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2281-2291.

Research output: Contribution to journalArticle

Gule, MK, Chen, Y, Sano, D, Frederick, MJ, Zhou, G, Zhao, M, Milas, ZL, Galer, CE, Henderson, YC, Jasser, SA, Schwartz, DL, Bankson, JA, Myers, JN & Lai, SY 2011, 'Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model', Clinical Cancer Research, vol. 17, no. 8, pp. 2281-2291. https://doi.org/10.1158/1078-0432.CCR-10-2762
Gule, Maria K. ; Chen, Yunyun ; Sano, Daisuke ; Frederick, Mitchell J. ; Zhou, Ge ; Zhao, Mei ; Milas, Zvonimir L. ; Galer, Chad E. ; Henderson, Ying C. ; Jasser, Samar A. ; Schwartz, David L. ; Bankson, James A. ; Myers, Jeffrey N. ; Lai, Stephen Y. / Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2281-2291.
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abstract = "Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60{\%} of all commonly used ATC cell lines, the significance of these past findings is unclear. Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature. Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3{\%} (P < 0.001) and 66.6{\%} (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control. Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.",
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T1 - Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model

AU - Gule, Maria K.

AU - Chen, Yunyun

AU - Sano, Daisuke

AU - Frederick, Mitchell J.

AU - Zhou, Ge

AU - Zhao, Mei

AU - Milas, Zvonimir L.

AU - Galer, Chad E.

AU - Henderson, Ying C.

AU - Jasser, Samar A.

AU - Schwartz, David L.

AU - Bankson, James A.

AU - Myers, Jeffrey N.

AU - Lai, Stephen Y.

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N2 - Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear. Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature. Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control. Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

AB - Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear. Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature. Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control. Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

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