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Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma
Angiosarcoma is an aggressive malignancy of vascular origin that occurs de novo or in the context of previous cancer therapy. Despite multi-modal aggressive treatment including surgical resection, chemotherapy, and radiation, five-year overall survival remains poor at 35%. Due to its rarity, little...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973867/ https://www.ncbi.nlm.nih.gov/pubmed/29872503 http://dx.doi.org/10.18632/oncotarget.25345 |
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author | Chadwick, Michelle L. Lane, Adam Thomas, Dana Smith, Amanda R. White, Angela R. Davidson, Dominique Feng, Yuxin Boscolo, Elisa Zheng, Yi Adams, Denise M. Gupta, Anita Veillette, André Chow, Lionel M.L. |
author_facet | Chadwick, Michelle L. Lane, Adam Thomas, Dana Smith, Amanda R. White, Angela R. Davidson, Dominique Feng, Yuxin Boscolo, Elisa Zheng, Yi Adams, Denise M. Gupta, Anita Veillette, André Chow, Lionel M.L. |
author_sort | Chadwick, Michelle L. |
collection | PubMed |
description | Angiosarcoma is an aggressive malignancy of vascular origin that occurs de novo or in the context of previous cancer therapy. Despite multi-modal aggressive treatment including surgical resection, chemotherapy, and radiation, five-year overall survival remains poor at 35%. Due to its rarity, little is known about its molecular pathology and clinical trials have been extremely difficult to conduct. Development of animal models for rare diseases like angiosarcoma is critical to improve our understanding of tumorigenesis and to test novel treatment regimens. A genetically engineered mouse model for angiosarcoma was generated by conditional deletion of Trp53, Pten, and Ptpn12 in endothelial cells. Tumors arising from these mice recapitulate the histology and molecular pathology of the human disease including hyperactivation of the PI3K/mTOR and MAPK signaling pathways. Treatment of tumor-bearing mice with mTOR or MEK inhibitors effectively inactivated signaling and resulted in reduced proliferation and elevated apoptosis leading to tumor regression. The effect of treatment on tumor growth was transient and proliferation was restored after a period of dormancy. However, combined inhibition of mTOR and MEK resulted in profound tumor regression which was sustained for the duration of treatment. These results suggest that angiosarcoma may be effectively treated by this drug combination. |
format | Online Article Text |
id | pubmed-5973867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-59738672018-06-05 Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma Chadwick, Michelle L. Lane, Adam Thomas, Dana Smith, Amanda R. White, Angela R. Davidson, Dominique Feng, Yuxin Boscolo, Elisa Zheng, Yi Adams, Denise M. Gupta, Anita Veillette, André Chow, Lionel M.L. Oncotarget Research Paper Angiosarcoma is an aggressive malignancy of vascular origin that occurs de novo or in the context of previous cancer therapy. Despite multi-modal aggressive treatment including surgical resection, chemotherapy, and radiation, five-year overall survival remains poor at 35%. Due to its rarity, little is known about its molecular pathology and clinical trials have been extremely difficult to conduct. Development of animal models for rare diseases like angiosarcoma is critical to improve our understanding of tumorigenesis and to test novel treatment regimens. A genetically engineered mouse model for angiosarcoma was generated by conditional deletion of Trp53, Pten, and Ptpn12 in endothelial cells. Tumors arising from these mice recapitulate the histology and molecular pathology of the human disease including hyperactivation of the PI3K/mTOR and MAPK signaling pathways. Treatment of tumor-bearing mice with mTOR or MEK inhibitors effectively inactivated signaling and resulted in reduced proliferation and elevated apoptosis leading to tumor regression. The effect of treatment on tumor growth was transient and proliferation was restored after a period of dormancy. However, combined inhibition of mTOR and MEK resulted in profound tumor regression which was sustained for the duration of treatment. These results suggest that angiosarcoma may be effectively treated by this drug combination. Impact Journals LLC 2018-05-15 /pmc/articles/PMC5973867/ /pubmed/29872503 http://dx.doi.org/10.18632/oncotarget.25345 Text en Copyright: © 2018 Chadwick et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Chadwick, Michelle L. Lane, Adam Thomas, Dana Smith, Amanda R. White, Angela R. Davidson, Dominique Feng, Yuxin Boscolo, Elisa Zheng, Yi Adams, Denise M. Gupta, Anita Veillette, André Chow, Lionel M.L. Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma |
title | Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma |
title_full | Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma |
title_fullStr | Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma |
title_full_unstemmed | Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma |
title_short | Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma |
title_sort | combined mtor and mek inhibition is an effective therapy in a novel mouse model for angiosarcoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973867/ https://www.ncbi.nlm.nih.gov/pubmed/29872503 http://dx.doi.org/10.18632/oncotarget.25345 |
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