Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788.
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 approximately 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.
Kim
Seungwon
S
Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Unit 441, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, USA.
Schiff
Bradley A
BA
Yigitbasi
Orhan G
OG
Doan
Dao
D
Jasser
Samar A
SA
Bekele
B Nebiyou
BN
Mandal
Mahitosh
M
Myers
Jeffrey N
JN
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy*; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D013997:Time Factors
D000970:Antineoplastic Agents; D011687:Purines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788; D017239:Paclitaxel