Revisiting the IGF-1R as a breast cancer target
Abstract 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 fa...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-05-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-017-0017-y |
| _version_ | 1797430848285310976 |
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| author | Roudy Chiminch Ekyalongo Douglas Yee |
| author_facet | Roudy Chiminch Ekyalongo Douglas Yee |
| author_sort | Roudy Chiminch Ekyalongo |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T09:33:28Z |
| format | Article |
| id | doaj.art-ff753cb1f1364c4681fe4a6c2ca7b956 |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T09:33:28Z |
| publishDate | 2017-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-ff753cb1f1364c4681fe4a6c2ca7b9562023-12-02T03:06:45ZengNature Portfolionpj Precision Oncology2397-768X2017-05-01111710.1038/s41698-017-0017-yRevisiting the IGF-1R as a breast cancer targetRoudy Chiminch Ekyalongo0Douglas Yee1Masonic Cancer Center, University of MinnesotaMasonic Cancer Center, University of MinnesotaAbstract 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.https://doi.org/10.1038/s41698-017-0017-y |
| spellingShingle | Roudy Chiminch Ekyalongo Douglas Yee Revisiting the IGF-1R as a breast cancer target npj Precision Oncology |
| 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 |
| url | https://doi.org/10.1038/s41698-017-0017-y |
| work_keys_str_mv | AT roudychiminchekyalongo revisitingtheigf1rasabreastcancertarget AT douglasyee revisitingtheigf1rasabreastcancertarget |