Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma

High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases reve...

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Vydáno v:	British journal of cancer Ročník 122; číslo 5; s. 624 - 629
Hlavní autoři:	Simpson, Aaron D., Soo, Ying Wei Jenetta, Rieunier, Guillaume, Aleksic, Tamara, Ansorge, Olaf, Jones, Chris, Macaulay, Valentine M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.03.2020 Nature Publishing Group
Témata:	631/67/1922 692/4028/67/1922 Apoptosis Biomedical and Life Sciences Biomedicine Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain Neoplasms - radiotherapy Brief Communication Cancer Research Cell Line, Tumor Cell lines DNA Damage Drug Resistance Epidemiology Glioma Glioma - genetics Glioma - metabolism Glioma - pathology Glioma - radiotherapy Humans Immunohistochemistry Insulin Insulin-like growth factors Molecular Medicine Neoplasm Grading Oncology Pediatrics Pyrazoles - pharmacology Radiation Tolerance - drug effects Radioresistance Receptor, IGF Type 1 - antagonists & inhibitors Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Signal Transduction - drug effects Tissue Array Analysis Triazines - pharmacology
ISSN:	0007-0920, 1532-1827, 1532-1827
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Abstract	High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R ( p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2–8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG.
AbstractList	High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R (p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2-8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG. High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R (p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2-8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG.High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R (p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2-8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG. High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked with radioresistance in other cancers. IGF-1R immunohistochemistry in 305 adult HGG (aHGG) and 103 paediatric/young adult HGG (pHGG) cases revealed significant association with adverse survival in pHGG, with median survival of 13.5 vs 29 months for pHGGs with moderate/strong vs negative/weak IGF-1R ( p = 0.011). Secondly, we tested IGF-1R inhibitor BMS-754807 in HGG cells, finding minimal radiosensitisation of 2/3 aHGG cell lines (dose enhancement ratios DERs < 1.60 at 2–8 Gy), and greater radiosensitisation of 2/2 pHGG cell lines (DERs ≤ 4.16). BMS-754807 did not influence radiation-induced apoptosis but perturbed the DNA damage response with altered induction/resolution of γH2AX, 53BP1 and RAD51 foci. These data indicate that IGF-1R promotes radioresistance in pHGG, potentially contributing to the association of IGF-1R with adverse outcome and suggesting IGF-1R as a candidate treatment target in pHGG.
Author	Macaulay, Valentine M. Soo, Ying Wei Jenetta Simpson, Aaron D. Aleksic, Tamara Rieunier, Guillaume Jones, Chris Ansorge, Olaf
Author_xml	– sequence: 1 givenname: Aaron D. surname: Simpson fullname: Simpson, Aaron D. organization: Department of Oncology, University of Oxford – sequence: 2 givenname: Ying Wei Jenetta surname: Soo fullname: Soo, Ying Wei Jenetta organization: Department of Oncology, University of Oxford – sequence: 3 givenname: Guillaume surname: Rieunier fullname: Rieunier, Guillaume organization: Department of Oncology, University of Oxford – sequence: 4 givenname: Tamara surname: Aleksic fullname: Aleksic, Tamara organization: Department of Oncology, University of Oxford – sequence: 5 givenname: Olaf surname: Ansorge fullname: Ansorge, Olaf organization: Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital – sequence: 6 givenname: Chris surname: Jones fullname: Jones, Chris organization: Institute of Cancer Research – sequence: 7 givenname: Valentine M. orcidid: 0000-0001-8659-0192 surname: Macaulay fullname: Macaulay, Valentine M. email: valentine.macaulay@oncology.ox.ac.uk organization: Department of Oncology, University of Oxford, Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
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Cites_doi	10.1016/j.semcancer.2015.07.003 10.1002/1878-0261.12053 10.1016/j.ijrobp.2004.03.005 10.1007/s11523-017-0514-5 10.1016/j.bmcl.2017.04.085 10.1038/bjc.2011.240 10.1002/em.21944 10.1259/bjr/83827377 10.1038/s41418-018-0129-0 10.1038/bjc.2015.242 10.1158/2159-8290.CD-12-0426 10.1158/1535-7163.MCT-09-0499 10.1038/bjc.2017.337 10.1038/onc.2013.460 10.1038/nrclinonc.2012.87 10.1016/j.mrfmmm.2017.07.011
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Snippet	High-grade glioma (HGG) is highly resistant to therapy, prompting us to investigate the contribution of insulin-like growth factor receptor (IGF-1R), linked...
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SubjectTerms	631/67/1922 692/4028/67/1922 Apoptosis Biomedical and Life Sciences Biomedicine Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain Neoplasms - radiotherapy Brief Communication Cancer Research Cell Line, Tumor Cell lines DNA Damage Drug Resistance Epidemiology Glioma Glioma - genetics Glioma - metabolism Glioma - pathology Glioma - radiotherapy Humans Immunohistochemistry Insulin Insulin-like growth factors Molecular Medicine Neoplasm Grading Oncology Pediatrics Pyrazoles - pharmacology Radiation Tolerance - drug effects Radioresistance Receptor, IGF Type 1 - antagonists & inhibitors Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Signal Transduction - drug effects Tissue Array Analysis Triazines - pharmacology
Title	Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma
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