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Revisiting the IGF-1R as a breast cancer target
The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 re...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687252/ https://www.ncbi.nlm.nih.gov/pubmed/29152592 http://dx.doi.org/10.1038/s41698-017-0017-y |
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author | Ekyalongo, Roudy Chiminch Yee, Douglas |
author_facet | Ekyalongo, Roudy Chiminch Yee, Douglas |
author_sort | Ekyalongo, Roudy Chiminch |
collection | PubMed |
description | The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3′-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions. |
format | Online Article Text |
id | pubmed-5687252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56872522017-11-15 Revisiting the IGF-1R as a breast cancer target Ekyalongo, Roudy Chiminch Yee, Douglas NPJ Precis Oncol Review Article The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3′-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions. Nature Publishing Group UK 2017-05-01 /pmc/articles/PMC5687252/ /pubmed/29152592 http://dx.doi.org/10.1038/s41698-017-0017-y Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Review Article Ekyalongo, Roudy Chiminch Yee, Douglas Revisiting the IGF-1R as a breast cancer target |
title | Revisiting the IGF-1R as a breast cancer target |
title_full | Revisiting the IGF-1R as a breast cancer target |
title_fullStr | Revisiting the IGF-1R as a breast cancer target |
title_full_unstemmed | Revisiting the IGF-1R as a breast cancer target |
title_short | Revisiting the IGF-1R as a breast cancer target |
title_sort | revisiting the igf-1r as a breast cancer target |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687252/ https://www.ncbi.nlm.nih.gov/pubmed/29152592 http://dx.doi.org/10.1038/s41698-017-0017-y |
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