Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer

Schiff, Bradley A.; McMurphy, Andrea Barber; Jasser, Samar A.; Younes, Mamoun; Doan, Dao; Yigitbasi, Orhan; Kim, Seungwon; Zhou, Ge; Mandal, Mahitosh; Bekele, B. Nebiyou; Holsinger, F. Christopher; Sherman, Steven I.; Yeung, Sai‐Ching Jim; El‐Naggar, Adel K.; Myers, Jeffrey N.

doi:10.1158/1078-0432.ccr-04-0690

Cited by 150 publications

(99 citation statements)

References 29 publications

(22 reference statements)

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“…In agreement with this, EGFR and VEGFR2 overexpression has been shown to be closely correlated to advanced tumor stage, metastasis, and poor clinical outcome in several human cancers. With respect to thyroid carcinomas, EGFR overexpression has been detected in most anaplastic tumors (Schiff et al 2004, Wiseman et al 2007, Elliott et al 2008 and to a much lower extent in PTCs (Schiff et al 2004, Murakawa et al 2005, Mitsiades et al 2006, Lim et al 2007, Elliott et al 2008. In PTC, EGFR expression has been associated to poor prognosis (Akslen & Varhaug 1995, Chen et al 1999, although not always (Lim et al 2007), and recent studies have suggested that EGFR inhibitors might be active against anaplastic thyroid carcinomas (Lopez et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Rodríguez‐Antona

Pallarés²,

Montero‐Conde³

et al. 2010

Endocrine-Related Cancer

118

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Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, PZ0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (PZ0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (PZ2.8!10 K8 ). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.

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Section: Discussionmentioning

confidence: 99%

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Rodríguez‐Antona

Pallarés²,

Montero‐Conde³

et al. 2010

Endocrine-Related Cancer

118

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“…EGFR is also frequently overexpressed in various types of thyroid carcinomas (11 -16) and this overexpression has been shown to correlate with poor prognosis in several studies (17,18). Recent work from our laboratory has shown that EGFR is overexpressed in ATC tumors as well (19). Consistent with these observations, inhibition of EGFR by using an anti-EGFR antibody and a small-molecule inhibitor of EGFR tyrosine kinase, AG 1478, has shown antiproliferative effects against thyroid carcinoma cell lines in vitro (20,21).…”

Section: Introductionmentioning

confidence: 96%

Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788

Kim¹,

Schiff²,

Yigitbasi³

et al. 2005

Molecular Cancer Therapeutics

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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 f6-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. [Mol Cancer Ther 2005;4(4):632 -40]

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“…EGFR is overexpressed in ATC cell lines in vitro and in vivo as well as human ATC specimens (Schiff et al 2004). Gefitinib inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of subcutaneous implant of ATC.…”

Section: Gefitinibmentioning

confidence: 98%

New therapeutic advances in the management of progressive thyroid cancer

Woyach¹,

Shah²

2009

Endocrine-Related Cancer

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The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodinerefractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I-III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.

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Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer

Cited by 150 publications

References 29 publications

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788

New therapeutic advances in the management of progressive thyroid cancer

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