Producción CyT
Congreso
Autoría
MARTIN, AYELEN
;
Fernández María Celia
;
Clement Florencia
;
Venara Marcela
;
García Lombardi Mercedes
;
Angulo Sergio
;
Sanchez Mariela
;
Bergadá Ignacio
;
Gutiérrez Mariana
;
Pennisi Patricia
Fecha
2019
Editorial y Lugar de Edición
Fundación Revista Medicina
Resumen
Información suministrada por el agente en
SIGEVA
In gliomas, the most frequent solid tumors in children, IGF1R nuclear localization is associated with high grade and increased risk of death. Chemotherapy after surgical resection is the mainstay of therapy. However, the best regimen needs to be determined. Aim: To characterize the impact of IGF1R nuclear localization in glioblastoma cells and the response to treatment with OSI906 (IGF1R/IR dual inhibitor) alone or in combination with Temozolomide (TMZ), a current adjuvant therapy in children. ...
In gliomas, the most frequent solid tumors in children, IGF1R nuclear localization is associated with high grade and increased risk of death. Chemotherapy after surgical resection is the mainstay of therapy. However, the best regimen needs to be determined. Aim: To characterize the impact of IGF1R nuclear localization in glioblastoma cells and the response to treatment with OSI906 (IGF1R/IR dual inhibitor) alone or in combination with Temozolomide (TMZ), a current adjuvant therapy in children. Methods: U87Mg cells were used to obtain clones expressing wild type GFP-IGF1R (WtU87) or GFP-IGF1R1025X1100X1120X to avoid IGF1R nuclear translocation (MutU87). Proliferation, wounding assays and qPCR were carried out with/without 50nM IGF1. Cells were cultured in complete media (10%FBS) with addition of OSI906 (0.5uM), TMZ (40 or 100uM) or the combination of drugs. Nude mice were injected sc with WtU87 or MutU87 cells. When tumors reached 150 mm3, OSI906 (25mg/kg, 3d) or TMZ (250mg/kg, single dose) were given by gavage. Results: IGF1 had no effect on WtU87 or MutU87cells proliferation or apoptosis after 5 days of culture. On the contrary, IGF1 stimulation increased motility, GLUT-1 & FASN expression, LDH activity and PDHc activation in WtU87compared to MutU87cells (p<0.05). All effects were blocked by preincubation with OSI906. Proliferation of WtU87 and MutU87cells decreased under TMZ40 or OSI906, and TMZ40+OSI906 had an additive effect only in WtU87 (P<0.02). TMZ100 had a strong inhibitory effect on both cell lines (p<0.001). In vivo studies showed similar trends. Conclusion: IGF1R nuclear translocation contributes to glioblastoma aggressiveness by increasing motility and metabolism of tumor cells. It also renders glioblastoma cells sensitive to IGF1R targeted therapy alone or in combination with TMZ, in vitro and in vivo. These results suggest that the use of IGF1R inhibitors in patients with nuclear localization for IGF1R, could be useful to reduce TMZ doses in children.
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Palabras Clave
OSI906IGF-1RGLIOBLASTOMACENTRAL NERVOUS SISTEM TUMORS