Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788

Seungwon Kim, Bradley A. Schiff, Orhan G. Yigitbasi, Dao Doan, Samar A. Jasser, B. Nebiyou Bekele, Mahitosh Mandal, Jeffrey N. Myers

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies with a mean survival of only 6 months. The poor prognosis of patients with ATC reflects the current lack of curative therapeutic options and the need for development of novel therapeutic strategies. In this study, we report the results of a preclinical study of AEE788, a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, against ATC. AEE788 was able to inhibit the proliferation and induce apoptosis of ATC cell lines in vitro. Administration of AEE788, alone and in combination with paclitaxel, to athymic nude mice bearing s.c. ATC xenografts inhibited the growth of ATC xenografts by 44% and 69%, respectively, compared with the control group. Furthermore, tumors from mice treated with AEE788, alone and in combination with paclitaxel, showed increase in apoptosis of tumor cells by ∼6- and 8-fold, respectively, compared with the control group. The microvessel density within the ATC xenografts was decreased by >80% in the mice treated with AEE788 alone and in combination with paclitaxel compared with the control group. Lastly, immunofluorescence microscopy showed the inhibition of EGFR autophosphorylation on the tumor cells as well as the inhibition of VEGFR-2 autophosphorylation on tumor endothelium. Considering the fact that curative options seldom exist for patients with ATC, concurrent inhibition of EGFR and VEGFR tyrosine kinases seems to be a valid and promising anticancer strategy for these patients.

Original languageEnglish (US)
Pages (from-to)632-640
Number of pages9
JournalMolecular Cancer Therapeutics
Volume4
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

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Molecular Targeted Therapy
Paclitaxel
Epidermal Growth Factor Receptor
Heterografts
Vascular Endothelial Growth Factor Receptor
Neoplasms
Nude Mice
Protein-Tyrosine Kinases
Control Groups
Apoptosis
Vascular Endothelial Growth Factor Receptor-2
Anaplastic Thyroid Carcinoma
AEE 788
Microvessels
Fluorescence Microscopy
Endothelium
Cell Line
Survival

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Kim, S., Schiff, B. A., Yigitbasi, O. G., Doan, D., Jasser, S. A., Bekele, B. N., ... Myers, J. N. (2005). Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788. Molecular Cancer Therapeutics, 4(4), 632-640. https://doi.org/10.1158/1535-7163.MCT-04-0293

Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788. / Kim, Seungwon; Schiff, Bradley A.; Yigitbasi, Orhan G.; Doan, Dao; Jasser, Samar A.; Bekele, B. Nebiyou; Mandal, Mahitosh; Myers, Jeffrey N.

In: Molecular Cancer Therapeutics, Vol. 4, No. 4, 04.2005, p. 632-640.

Research output: Contribution to journalArticle

Kim, S, Schiff, BA, Yigitbasi, OG, Doan, D, Jasser, SA, Bekele, BN, Mandal, M & Myers, JN 2005, 'Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788', Molecular Cancer Therapeutics, vol. 4, no. 4, pp. 632-640. https://doi.org/10.1158/1535-7163.MCT-04-0293
Kim, Seungwon ; Schiff, Bradley A. ; Yigitbasi, Orhan G. ; Doan, Dao ; Jasser, Samar A. ; Bekele, B. Nebiyou ; Mandal, Mahitosh ; Myers, Jeffrey N. / Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 4. pp. 632-640.
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