A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma

Epidermal growth factor receptor (EGFR) is often overexpressed in head and neck squamous cell carcinoma (HNSCC) and represents a top candidate for targeted HNSCC therapy. However, the clinical effectiveness of current Food and Drug Administration (FDA)‐approved drugs targeting EGFR is moderate, and...

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Main Authors: Zeng Qi, Yue Qiu, Zhaohui Wang, Huiping Zhang, Ling Lu, Yanqiu Liu, David Mathes, Elizabeth A. Pomfret, Dexiang Gao, Shi‐Long Lu, Zhirui Wang
Format: Article
Language:English
Published: Wiley 2021-04-01
Series:Molecular Oncology
Subjects:
EGF
Online Access:https://doi.org/10.1002/1878-0261.12919
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spelling doaj-bfc0a175b0814640b88f3365da6e31272021-04-07T06:04:57ZengWileyMolecular Oncology1574-78911878-02612021-04-011541054106810.1002/1878-0261.12919A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinomaZeng Qi0Yue Qiu1Zhaohui Wang2Huiping Zhang3Ling Lu4Yanqiu Liu5David Mathes6Elizabeth A. Pomfret7Dexiang Gao8Shi‐Long Lu9Zhirui Wang10Division of Plastic and Reconstructive Surgery Department of Surgery School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADepartment of Otolaryngology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADivision of Plastic and Reconstructive Surgery Department of Surgery School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADivision of Plastic and Reconstructive Surgery Department of Surgery School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADepartment of Otolaryngology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADepartment of Otolaryngology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADivision of Plastic and Reconstructive Surgery Department of Surgery School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADivision of Transplant Surgery Department of Surgery School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADepartment of Biostatics School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADepartment of Otolaryngology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USADivision of Plastic and Reconstructive Surgery Department of Surgery School of Medicine University of Colorado Anschutz Medical Campus Aurora CO USAEpidermal growth factor receptor (EGFR) is often overexpressed in head and neck squamous cell carcinoma (HNSCC) and represents a top candidate for targeted HNSCC therapy. However, the clinical effectiveness of current Food and Drug Administration (FDA)‐approved drugs targeting EGFR is moderate, and the overall survival rate for HNSCC patients remains low. Therefore, more effective treatments are urgently needed. In this study, we generated a novel diphtheria toxin‐based bivalent human epidermal growth factor fusion toxin (bi‐EGF‐IT) to treat EGFR‐expressing HNSCC. Bi‐EGF‐IT was tested for in vitro binding affinity, cytotoxicity, and specificity using 14 human EGFR‐expressing HNSCC cell lines and three human EGFR‐negative cancer cell lines. Bi‐EGF‐IT had increased binding affinity for EGFR‐expressing HNSCC compared with the monovalent version (mono‐EGF‐IT), and both versions specifically depleted EGFR‐positive HNSCC, but not EGFR‐negative cell lines, in vitro. Bi‐EGF‐IT exhibited a comparable potency to that of the FDA‐approved EGFR inhibitor, erlotinib, for inhibiting HNSCC tumor growth in vivo using both subcutaneous and orthotopic HNSCC xenograft mouse models. When tested in an experimental metastasis model, survival was significantly longer in the bi‐EGF‐IT treatment group than the erlotinib treatment group, with a significantly reduced number of metastases compared with mono‐EGF‐IT. In addition, in vivo off‐target toxicities were significantly reduced in the bi‐EGF‐IT treatment group compared with the mono‐EGF‐IT group. These results demonstrate that bi‐EGF‐IT is more effective and markedly less toxic at inhibiting primary HNSCC tumor growth and metastasis than mono‐EGF‐IT and erlotinib. Thus, the novel bi‐EGF‐IT is a promising drug candidate for further development.https://doi.org/10.1002/1878-0261.12919diphtheria toxinEGFEGFRfusion toxinhead and neck cancerHNSCC
collection DOAJ
language English
format Article
sources DOAJ
author Zeng Qi
Yue Qiu
Zhaohui Wang
Huiping Zhang
Ling Lu
Yanqiu Liu
David Mathes
Elizabeth A. Pomfret
Dexiang Gao
Shi‐Long Lu
Zhirui Wang
spellingShingle Zeng Qi
Yue Qiu
Zhaohui Wang
Huiping Zhang
Ling Lu
Yanqiu Liu
David Mathes
Elizabeth A. Pomfret
Dexiang Gao
Shi‐Long Lu
Zhirui Wang
A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma
Molecular Oncology
diphtheria toxin
EGF
EGFR
fusion toxin
head and neck cancer
HNSCC
author_facet Zeng Qi
Yue Qiu
Zhaohui Wang
Huiping Zhang
Ling Lu
Yanqiu Liu
David Mathes
Elizabeth A. Pomfret
Dexiang Gao
Shi‐Long Lu
Zhirui Wang
author_sort Zeng Qi
title A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma
title_short A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma
title_full A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma
title_fullStr A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma
title_full_unstemmed A novel diphtheria toxin‐based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma
title_sort novel diphtheria toxin‐based bivalent human egf fusion toxin for treatment of head and neck squamous cell carcinoma
publisher Wiley
series Molecular Oncology
issn 1574-7891
1878-0261
publishDate 2021-04-01
description Epidermal growth factor receptor (EGFR) is often overexpressed in head and neck squamous cell carcinoma (HNSCC) and represents a top candidate for targeted HNSCC therapy. However, the clinical effectiveness of current Food and Drug Administration (FDA)‐approved drugs targeting EGFR is moderate, and the overall survival rate for HNSCC patients remains low. Therefore, more effective treatments are urgently needed. In this study, we generated a novel diphtheria toxin‐based bivalent human epidermal growth factor fusion toxin (bi‐EGF‐IT) to treat EGFR‐expressing HNSCC. Bi‐EGF‐IT was tested for in vitro binding affinity, cytotoxicity, and specificity using 14 human EGFR‐expressing HNSCC cell lines and three human EGFR‐negative cancer cell lines. Bi‐EGF‐IT had increased binding affinity for EGFR‐expressing HNSCC compared with the monovalent version (mono‐EGF‐IT), and both versions specifically depleted EGFR‐positive HNSCC, but not EGFR‐negative cell lines, in vitro. Bi‐EGF‐IT exhibited a comparable potency to that of the FDA‐approved EGFR inhibitor, erlotinib, for inhibiting HNSCC tumor growth in vivo using both subcutaneous and orthotopic HNSCC xenograft mouse models. When tested in an experimental metastasis model, survival was significantly longer in the bi‐EGF‐IT treatment group than the erlotinib treatment group, with a significantly reduced number of metastases compared with mono‐EGF‐IT. In addition, in vivo off‐target toxicities were significantly reduced in the bi‐EGF‐IT treatment group compared with the mono‐EGF‐IT group. These results demonstrate that bi‐EGF‐IT is more effective and markedly less toxic at inhibiting primary HNSCC tumor growth and metastasis than mono‐EGF‐IT and erlotinib. Thus, the novel bi‐EGF‐IT is a promising drug candidate for further development.
topic diphtheria toxin
EGF
EGFR
fusion toxin
head and neck cancer
HNSCC
url https://doi.org/10.1002/1878-0261.12919
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