Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma
Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypot...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/12/3568 |
| _version_ | 1797546250348789760 |
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| author | Stefanie de Groot Bas Röttgering Hans Gelderblom Hanno Pijl Karoly Szuhai Judith R. Kroep |
| author_facet | Stefanie de Groot Bas Röttgering Hans Gelderblom Hanno Pijl Karoly Szuhai Judith R. Kroep |
| author_sort | Stefanie de Groot |
| collection | DOAJ |
| description | Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor. |
| first_indexed | 2024-03-10T14:27:22Z |
| format | Article |
| id | doaj.art-a37c8613e6314bfea6b4930acb83c4ac |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:27:22Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a37c8613e6314bfea6b4930acb83c4ac2023-11-20T22:53:55ZengMDPI AGCancers2072-66942020-11-011212356810.3390/cancers12123568Unraveling the Resistance of IGF-Pathway Inhibition in Ewing SarcomaStefanie de Groot0Bas Röttgering1Hans Gelderblom2Hanno Pijl3Karoly Szuhai4Judith R. Kroep5Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The NetherlandsDepartment of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The NetherlandsDepartment of Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The NetherlandsDepartment of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The NetherlandsInsulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.https://www.mdpi.com/2072-6694/12/12/3568IGF1IGF2IGF1RinsulinINSRIRA |
| spellingShingle | Stefanie de Groot Bas Röttgering Hans Gelderblom Hanno Pijl Karoly Szuhai Judith R. Kroep Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma Cancers IGF1 IGF2 IGF1R insulin INSR IRA |
| title | Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma |
| title_full | Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma |
| title_fullStr | Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma |
| title_full_unstemmed | Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma |
| title_short | Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma |
| title_sort | unraveling the resistance of igf pathway inhibition in ewing sarcoma |
| topic | IGF1 IGF2 IGF1R insulin INSR IRA |
| url | https://www.mdpi.com/2072-6694/12/12/3568 |
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