Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with NVP-AEE788 for the treatment of aggressive follicular thyroid cancer
- PMID: 16740767
- DOI: 10.1158/1078-0432.CCR-06-0793
Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with NVP-AEE788 for the treatment of aggressive follicular thyroid cancer
Abstract
Purpose: Patients with radioiodine-resistant follicular thyroid cancer (FTC) have a poor prognosis, if metastasized, with currently available treatment modalities. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) and their receptors (EGFR and VEGFR) have been reported to be overexpressed in FTC and have been implicated in FTC development. We hypothesized that inhibiting the phosphorylation of EGFR and VEGFR by treatment with NVP-AEE788 (AEE788), a novel dual specific EGFR and VEGFR inhibitor, either alone or in combination with paclitaxel, would inhibit the growth of FTC xenografts in an orthotopic nude mouse model.
Experimental design: To confirm previous reports, EGF and EGFR expression and vascularity were analyzed in human samples of FTC, Hürthle cell carcinoma, and normal thyroid tissues. EGFR expression in four FTC cell lines was measured using Western blotting. The antitumor effect of AEE788 on FTC cells in vitro was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and Western blotting. The effect of AEE788, alone and in combination with paclitaxel, on FTC tumor growth in an orthotopic nude mouse model was also investigated. Immunohistochemical analysis of EGFR and VEGFR signaling status, cell proliferation, apoptosis, and microvessel density was done.
Results: EGF, EGFR, and vascularity were increased in human thyroid tumor samples and EGFR was increased in FTC cells. AEE788 inhibited FTC cell growth in vitro and reduced the phosphorylation status of EGFR, VEGFR, and two downstream targets, AKT and mitogen-activated protein kinase, in FTC cells. AEE788 alone and, to a greater extent, AEE788 plus paclitaxel suppressed FTC tumor growth in the thyroids of nude mice.
Conclusion: Dual inhibition of EGFR and VEGFR by AEE788 could represent a novel approach to the treatment of radioiodine-resistant FTC.
Similar articles
-
Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation.Cancer Res. 2005 Jun 1;65(11):4716-27. doi: 10.1158/0008-5472.CAN-04-4196. Cancer Res. 2005. PMID: 15930290
-
Antivascular therapy for orthotopic human ovarian carcinoma through blockade of the vascular endothelial growth factor and epidermal growth factor receptors.Clin Cancer Res. 2005 Jul 1;11(13):4923-33. doi: 10.1158/1078-0432.CCR-04-2060. Clin Cancer Res. 2005. PMID: 16000591
-
AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity.Cancer Res. 2004 Jul 15;64(14):4931-41. doi: 10.1158/0008-5472.CAN-03-3681. Cancer Res. 2004. PMID: 15256466
-
Combined inhibition of the VEGFR and EGFR signaling pathways in the treatment of NSCLC.Oncologist. 2009 Apr;14(4):399-411. doi: 10.1634/theoncologist.2008-0276. Epub 2009 Apr 8. Oncologist. 2009. PMID: 19357226 Review.
-
Targeted agents for the treatment of advanced renal cell carcinoma.Cancer. 2005 Dec 1;104(11):2323-33. doi: 10.1002/cncr.21453. Cancer. 2005. PMID: 16240452 Review.
Cited by
-
Epidermal growth factor receptor activation confers resistance to lenvatinib in thyroid cancer cells.Cancer Sci. 2022 Sep;113(9):3193-3210. doi: 10.1111/cas.15465. Epub 2022 Jul 12. Cancer Sci. 2022. PMID: 35723021 Free PMC article.
-
Phase 2 study of vascular endothelial growth factor trap for the treatment of metastatic thyroid cancer.Cancer. 2019 Sep 1;125(17):2984-2990. doi: 10.1002/cncr.32046. Epub 2019 Jun 7. Cancer. 2019. PMID: 31174237 Free PMC article. Clinical Trial.
-
Expression of Vascular Endothelial Growth Factor and Its Receptors in Thyroid Nodular Hyperplasia and Papillary Thyroid Carcinoma: A Tertiary Health Care Centre Based Study.Asian Pac J Cancer Prev. 2019 Jan 25;20(1):277-282. doi: 10.31557/APJCP.2019.20.1.277. Asian Pac J Cancer Prev. 2019. PMID: 30678450 Free PMC article.
-
Current Trends in Cancer Nanotheranostics: Metallic, Polymeric, and Lipid-Based Systems.Pharmaceutics. 2019 Jan 8;11(1):22. doi: 10.3390/pharmaceutics11010022. Pharmaceutics. 2019. PMID: 30625999 Free PMC article. Review.
-
Selective use of vandetanib in the treatment of thyroid cancer.Drug Des Devel Ther. 2015 Jul 3;9:3459-70. doi: 10.2147/DDDT.S72495. eCollection 2015. Drug Des Devel Ther. 2015. PMID: 26170630 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous