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Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis. Human papilloma virus (HPV) infection is associated with 20% HNSCC, and 50% of oropharyngeal carcinoma. HPV16 type is detected in 90% of all HPV+ HNSCC. Recently we suggeste...

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Autores principales: Harris, Matthew, Wang, Xing Guo, Jiang, Zewei, Goldberg, Gary L, Casadevall, Arturo, Dadachova, Ekaterina
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046925/
https://www.ncbi.nlm.nih.gov/pubmed/21314983
http://dx.doi.org/10.1186/1758-3284-3-9
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author Harris, Matthew
Wang, Xing Guo
Jiang, Zewei
Goldberg, Gary L
Casadevall, Arturo
Dadachova, Ekaterina
author_facet Harris, Matthew
Wang, Xing Guo
Jiang, Zewei
Goldberg, Gary L
Casadevall, Arturo
Dadachova, Ekaterina
author_sort Harris, Matthew
collection PubMed
description BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis. Human papilloma virus (HPV) infection is associated with 20% HNSCC, and 50% of oropharyngeal carcinoma. HPV16 type is detected in 90% of all HPV+ HNSCC. Recently we suggested a fundamentally different approach to treatment of cancers of viral origin by targeting viral antigens on cancer cells with radiolabeled antibodies (mAbs) which promises exquisite specificity of treatment. We aimed at extending this approach to HPV-related head and neck cancer by performing radioimmunotherapy (RIT) targeting E6 and E7 oncogenes with radiolabeled mAbs. METHODS: We first aimed at developing HPV16+ cell line and animal model for RIT of HNSCC as at present there are no commercially available HPV16+ HNSCC cell lines and there is only one HPV+ cell line among the collection maintained by Dusseldorf, Michigan and Turku groups. Commercially available HNSCC cell line FaDu was transfected with pLXSN16E6E7 vector containing HPV16 E6 and E7 genes. Generated novel cell lines were evaluated by PCR and western blot and the tumorigenecity was assessed in nude mice. Proof of principle RIT targeting E6 oncoprotein in 2A3 tumor-bearing nude mice was conducted using unlabeled or 188-Rhenium ((188)Re)-labeled C1P5 mAb to E6. RESULTS: Novel HPV16+ 2A3 cell line reliably expressed E6 oncoprotein. E6 expression was modifiable with proteasome inhibitor MG132 in a dose-dependent manner. The levels of E6 expression in 2A3 cell line were estimated to be around 200 HPV copies per cell. The HPV16+ 2A3 cell line preserved 100% tumorigenicity of parent FaDu cells in nude mice. During RIT of 2A3 tumors in nude mice the relatively low dose of 200 μCi (188)Re-C1P5 mAb was effective in decreasing the tumor growth in comparison with untreated controls. Unlabeled C1P5 mAb also caused some decrease in tumor progression, however, much less pronounced than (188)Re-C1P5 mAb. CONCLUSIONS: We describe a proof-of-principle RIT study targeting HPV16 E6 oncoprotein with radiolabeled mAb to E6 in a stably transformed HPV16+ HNSCC cell line and tumor model in nude mice, and demonstrate potential utility of RIT as a novel molecular targeted therapy for HNSCC.
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spelling pubmed-30469252011-03-02 Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line Harris, Matthew Wang, Xing Guo Jiang, Zewei Goldberg, Gary L Casadevall, Arturo Dadachova, Ekaterina Head Neck Oncol Research BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis. Human papilloma virus (HPV) infection is associated with 20% HNSCC, and 50% of oropharyngeal carcinoma. HPV16 type is detected in 90% of all HPV+ HNSCC. Recently we suggested a fundamentally different approach to treatment of cancers of viral origin by targeting viral antigens on cancer cells with radiolabeled antibodies (mAbs) which promises exquisite specificity of treatment. We aimed at extending this approach to HPV-related head and neck cancer by performing radioimmunotherapy (RIT) targeting E6 and E7 oncogenes with radiolabeled mAbs. METHODS: We first aimed at developing HPV16+ cell line and animal model for RIT of HNSCC as at present there are no commercially available HPV16+ HNSCC cell lines and there is only one HPV+ cell line among the collection maintained by Dusseldorf, Michigan and Turku groups. Commercially available HNSCC cell line FaDu was transfected with pLXSN16E6E7 vector containing HPV16 E6 and E7 genes. Generated novel cell lines were evaluated by PCR and western blot and the tumorigenecity was assessed in nude mice. Proof of principle RIT targeting E6 oncoprotein in 2A3 tumor-bearing nude mice was conducted using unlabeled or 188-Rhenium ((188)Re)-labeled C1P5 mAb to E6. RESULTS: Novel HPV16+ 2A3 cell line reliably expressed E6 oncoprotein. E6 expression was modifiable with proteasome inhibitor MG132 in a dose-dependent manner. The levels of E6 expression in 2A3 cell line were estimated to be around 200 HPV copies per cell. The HPV16+ 2A3 cell line preserved 100% tumorigenicity of parent FaDu cells in nude mice. During RIT of 2A3 tumors in nude mice the relatively low dose of 200 μCi (188)Re-C1P5 mAb was effective in decreasing the tumor growth in comparison with untreated controls. Unlabeled C1P5 mAb also caused some decrease in tumor progression, however, much less pronounced than (188)Re-C1P5 mAb. CONCLUSIONS: We describe a proof-of-principle RIT study targeting HPV16 E6 oncoprotein with radiolabeled mAb to E6 in a stably transformed HPV16+ HNSCC cell line and tumor model in nude mice, and demonstrate potential utility of RIT as a novel molecular targeted therapy for HNSCC. BioMed Central 2011-02-12 /pmc/articles/PMC3046925/ /pubmed/21314983 http://dx.doi.org/10.1186/1758-3284-3-9 Text en Copyright ©2011 Harris et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Harris, Matthew
Wang, Xing Guo
Jiang, Zewei
Goldberg, Gary L
Casadevall, Arturo
Dadachova, Ekaterina
Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
title Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
title_full Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
title_fullStr Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
title_full_unstemmed Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
title_short Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line
title_sort radioimmunotherapy of experimental head and neck squamous cell carcinoma (hnscc) with e6-specific antibody using a novel hpv-16 positive hnscc cell line
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046925/
https://www.ncbi.nlm.nih.gov/pubmed/21314983
http://dx.doi.org/10.1186/1758-3284-3-9
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