Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies

Autores
Fernández, María Celia; Martin, Ayelen; Clément, Florencia; Venara, Marcela Cristina; García Lombardi, M.; Bergadá, Ignacio; Gutiérrez, Mariana Lilián; Pennisi, Patricia Alejandra
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Background: CNS tumors are the most frequent solid tumors in children. In paediatric gliomas, IGF-1R nuclear localization was significantly associated with both high grade tumours and increased risk of death and contributed to the aggressive phenotype of glioblastoma by increasing motility and metabolism of tumor cells rather than increasing its proliferation. For children chemotherapy after surgical resection is the mainstay of therapy. However, the best regimen needs to be determined.Aim: To characterize the response of glioblastoma cells to treatment with OSI906 (IGF1R/IR dual inhibitor) alone or in combination with Temozolomide used as a current adjuvant chemotherapy for paediatric patients.Methods: stably transfected U87Mg glioblastoma cells with 5 times basal expression of wild type mature GFP-IGF1R fusion protein (wt-IGF1R, WtU87) or GFP-IGF1R fusion protein mutated in Lys1025-1100-1120 to avoid IGF-1R nuclear translocation (m-IGF1R, MutU87) were used for in vitro and in vivo assays. Proliferation assays were carried out for 3 days using complete media (10%FBS), or in the presence of IGF-1R/IR inhibitor OSI906 (0.5uM), Temozolomide (TMZ, 40 or 100uM) or the combination of both treatments. Male nude mice were injected for in vivo experiments (1,5e6cells/flank/mice). OSI906 (50mg/kg) and TMZ (400mg/kg) were given by gavage once daily or as a single dose respectively. Treatments were started when tumors reached 150 mm3.Results: After 24 h of culture, MutU87 cells showed decreased proliferation when treated with TMZ40 and OSI906; OSI906 had an additive effect when combined with TMZ40 compared to control condition. However, cells resumed proliferation after 3 days in culture. On the contrary, treatment with TMZ100 had a strong inhibitory effect, that was not increased by the combination with OSI906. WtU87 treated with TMZ40 or 100 also resumed proliferation after 24 h treatment, although the total number of cells was decreased compared to control. OSI906 was able to abolish proliferation of WtU87 cells when used alone or in combination with TMZ 40 or 100, having the latter the strongest effect. In vivo studies showed similar trends.Conclusion: The capacity of the IGF1R to translocate to the nucleus, renders glioblastoma cells sensitive to the IGF-1R targeted therapy alone or in combination with TMZ, in vitro and in vivo. These results suggest that the use of IGF1R inhibitors in pediatric patients showing nuclear localization for this receptor, could be useful to reduce TMZ doses and or avoid radiotherapy in children.
Fil: Fernández, María Celia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Martin, Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Clément, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Venara, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: García Lombardi, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Bergadá, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Gutiérrez, Mariana Lilián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Pennisi, Patricia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
XXVIII Congreso Latinoamericano de Endocrinología Pediátrica
Florianópolis
Brasil
Sociedad Latinoamericana de Endocrinología Pediátrica
Materia
IGF1R
OSI906
GLIOBLASTOMA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/139703
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo StudiesFernández, María CeliaMartin, AyelenClément, FlorenciaVenara, Marcela CristinaGarcía Lombardi, M.Bergadá, IgnacioGutiérrez, Mariana LiliánPennisi, Patricia AlejandraIGF1ROSI906GLIOBLASTOMAhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: CNS tumors are the most frequent solid tumors in children. In paediatric gliomas, IGF-1R nuclear localization was significantly associated with both high grade tumours and increased risk of death and contributed to the aggressive phenotype of glioblastoma by increasing motility and metabolism of tumor cells rather than increasing its proliferation. For children chemotherapy after surgical resection is the mainstay of therapy. However, the best regimen needs to be determined.Aim: To characterize the response of glioblastoma cells to treatment with OSI906 (IGF1R/IR dual inhibitor) alone or in combination with Temozolomide used as a current adjuvant chemotherapy for paediatric patients.Methods: stably transfected U87Mg glioblastoma cells with 5 times basal expression of wild type mature GFP-IGF1R fusion protein (wt-IGF1R, WtU87) or GFP-IGF1R fusion protein mutated in Lys1025-1100-1120 to avoid IGF-1R nuclear translocation (m-IGF1R, MutU87) were used for in vitro and in vivo assays. Proliferation assays were carried out for 3 days using complete media (10%FBS), or in the presence of IGF-1R/IR inhibitor OSI906 (0.5uM), Temozolomide (TMZ, 40 or 100uM) or the combination of both treatments. Male nude mice were injected for in vivo experiments (1,5e6cells/flank/mice). OSI906 (50mg/kg) and TMZ (400mg/kg) were given by gavage once daily or as a single dose respectively. Treatments were started when tumors reached 150 mm3.Results: After 24 h of culture, MutU87 cells showed decreased proliferation when treated with TMZ40 and OSI906; OSI906 had an additive effect when combined with TMZ40 compared to control condition. However, cells resumed proliferation after 3 days in culture. On the contrary, treatment with TMZ100 had a strong inhibitory effect, that was not increased by the combination with OSI906. WtU87 treated with TMZ40 or 100 also resumed proliferation after 24 h treatment, although the total number of cells was decreased compared to control. OSI906 was able to abolish proliferation of WtU87 cells when used alone or in combination with TMZ 40 or 100, having the latter the strongest effect. In vivo studies showed similar trends.Conclusion: The capacity of the IGF1R to translocate to the nucleus, renders glioblastoma cells sensitive to the IGF-1R targeted therapy alone or in combination with TMZ, in vitro and in vivo. These results suggest that the use of IGF1R inhibitors in pediatric patients showing nuclear localization for this receptor, could be useful to reduce TMZ doses and or avoid radiotherapy in children.Fil: Fernández, María Celia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Martin, Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Clément, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Venara, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: García Lombardi, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Bergadá, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Gutiérrez, Mariana Lilián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Pennisi, Patricia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaXXVIII Congreso Latinoamericano de Endocrinología PediátricaFlorianópolisBrasilSociedad Latinoamericana de Endocrinología PediátricaKarger2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/139703Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies; XXVIII Congreso Latinoamericano de Endocrinología Pediátrica; Florianópolis; Brasil; 2019; 12-121663-2818CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://doi.org/10.1159/000504400Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:22Zoai:ri.conicet.gov.ar:11336/139703instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:05:22.921CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
title Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
spellingShingle Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
Fernández, María Celia
IGF1R
OSI906
GLIOBLASTOMA
title_short Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
title_full Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
title_fullStr Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
title_full_unstemmed Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
title_sort Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies
dc.creator.none.fl_str_mv Fernández, María Celia
Martin, Ayelen
Clément, Florencia
Venara, Marcela Cristina
García Lombardi, M.
Bergadá, Ignacio
Gutiérrez, Mariana Lilián
Pennisi, Patricia Alejandra
author Fernández, María Celia
author_facet Fernández, María Celia
Martin, Ayelen
Clément, Florencia
Venara, Marcela Cristina
García Lombardi, M.
Bergadá, Ignacio
Gutiérrez, Mariana Lilián
Pennisi, Patricia Alejandra
author_role author
author2 Martin, Ayelen
Clément, Florencia
Venara, Marcela Cristina
García Lombardi, M.
Bergadá, Ignacio
Gutiérrez, Mariana Lilián
Pennisi, Patricia Alejandra
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv IGF1R
OSI906
GLIOBLASTOMA
topic IGF1R
OSI906
GLIOBLASTOMA
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: CNS tumors are the most frequent solid tumors in children. In paediatric gliomas, IGF-1R nuclear localization was significantly associated with both high grade tumours and increased risk of death and contributed to the aggressive phenotype of glioblastoma by increasing motility and metabolism of tumor cells rather than increasing its proliferation. For children chemotherapy after surgical resection is the mainstay of therapy. However, the best regimen needs to be determined.Aim: To characterize the response of glioblastoma cells to treatment with OSI906 (IGF1R/IR dual inhibitor) alone or in combination with Temozolomide used as a current adjuvant chemotherapy for paediatric patients.Methods: stably transfected U87Mg glioblastoma cells with 5 times basal expression of wild type mature GFP-IGF1R fusion protein (wt-IGF1R, WtU87) or GFP-IGF1R fusion protein mutated in Lys1025-1100-1120 to avoid IGF-1R nuclear translocation (m-IGF1R, MutU87) were used for in vitro and in vivo assays. Proliferation assays were carried out for 3 days using complete media (10%FBS), or in the presence of IGF-1R/IR inhibitor OSI906 (0.5uM), Temozolomide (TMZ, 40 or 100uM) or the combination of both treatments. Male nude mice were injected for in vivo experiments (1,5e6cells/flank/mice). OSI906 (50mg/kg) and TMZ (400mg/kg) were given by gavage once daily or as a single dose respectively. Treatments were started when tumors reached 150 mm3.Results: After 24 h of culture, MutU87 cells showed decreased proliferation when treated with TMZ40 and OSI906; OSI906 had an additive effect when combined with TMZ40 compared to control condition. However, cells resumed proliferation after 3 days in culture. On the contrary, treatment with TMZ100 had a strong inhibitory effect, that was not increased by the combination with OSI906. WtU87 treated with TMZ40 or 100 also resumed proliferation after 24 h treatment, although the total number of cells was decreased compared to control. OSI906 was able to abolish proliferation of WtU87 cells when used alone or in combination with TMZ 40 or 100, having the latter the strongest effect. In vivo studies showed similar trends.Conclusion: The capacity of the IGF1R to translocate to the nucleus, renders glioblastoma cells sensitive to the IGF-1R targeted therapy alone or in combination with TMZ, in vitro and in vivo. These results suggest that the use of IGF1R inhibitors in pediatric patients showing nuclear localization for this receptor, could be useful to reduce TMZ doses and or avoid radiotherapy in children.
Fil: Fernández, María Celia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Martin, Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Clément, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Venara, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: García Lombardi, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Bergadá, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Gutiérrez, Mariana Lilián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
Fil: Pennisi, Patricia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina
XXVIII Congreso Latinoamericano de Endocrinología Pediátrica
Florianópolis
Brasil
Sociedad Latinoamericana de Endocrinología Pediátrica
description Background: CNS tumors are the most frequent solid tumors in children. In paediatric gliomas, IGF-1R nuclear localization was significantly associated with both high grade tumours and increased risk of death and contributed to the aggressive phenotype of glioblastoma by increasing motility and metabolism of tumor cells rather than increasing its proliferation. For children chemotherapy after surgical resection is the mainstay of therapy. However, the best regimen needs to be determined.Aim: To characterize the response of glioblastoma cells to treatment with OSI906 (IGF1R/IR dual inhibitor) alone or in combination with Temozolomide used as a current adjuvant chemotherapy for paediatric patients.Methods: stably transfected U87Mg glioblastoma cells with 5 times basal expression of wild type mature GFP-IGF1R fusion protein (wt-IGF1R, WtU87) or GFP-IGF1R fusion protein mutated in Lys1025-1100-1120 to avoid IGF-1R nuclear translocation (m-IGF1R, MutU87) were used for in vitro and in vivo assays. Proliferation assays were carried out for 3 days using complete media (10%FBS), or in the presence of IGF-1R/IR inhibitor OSI906 (0.5uM), Temozolomide (TMZ, 40 or 100uM) or the combination of both treatments. Male nude mice were injected for in vivo experiments (1,5e6cells/flank/mice). OSI906 (50mg/kg) and TMZ (400mg/kg) were given by gavage once daily or as a single dose respectively. Treatments were started when tumors reached 150 mm3.Results: After 24 h of culture, MutU87 cells showed decreased proliferation when treated with TMZ40 and OSI906; OSI906 had an additive effect when combined with TMZ40 compared to control condition. However, cells resumed proliferation after 3 days in culture. On the contrary, treatment with TMZ100 had a strong inhibitory effect, that was not increased by the combination with OSI906. WtU87 treated with TMZ40 or 100 also resumed proliferation after 24 h treatment, although the total number of cells was decreased compared to control. OSI906 was able to abolish proliferation of WtU87 cells when used alone or in combination with TMZ 40 or 100, having the latter the strongest effect. In vivo studies showed similar trends.Conclusion: The capacity of the IGF1R to translocate to the nucleus, renders glioblastoma cells sensitive to the IGF-1R targeted therapy alone or in combination with TMZ, in vitro and in vivo. These results suggest that the use of IGF1R inhibitors in pediatric patients showing nuclear localization for this receptor, could be useful to reduce TMZ doses and or avoid radiotherapy in children.
publishDate 2019
dc.date.none.fl_str_mv 2019
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status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/139703
Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies; XXVIII Congreso Latinoamericano de Endocrinología Pediátrica; Florianópolis; Brasil; 2019; 12-12
1663-2818
CONICET Digital
CONICET
url http://hdl.handle.net/11336/139703
identifier_str_mv Inhibition Of IGF1R by IGF-1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: In Vitro & in Vivo Studies; XXVIII Congreso Latinoamericano de Endocrinología Pediátrica; Florianópolis; Brasil; 2019; 12-12
1663-2818
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Karger
publisher.none.fl_str_mv Karger
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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