IGF-1R nuclear localization in paediatric glioblastoma: phenotypic characterization and use of IGF-1R/IR inhibitor OSI906 as a targeted therapy

CLEMENT FLORENCIA; ANGULO SERGIO; GUTIÉRREZ MARIANA; MARTIN AYELEN; VENARA MARCELA; SANCHEZ MARIELA; PENNISI PATRICIA; FERNÁNDEZ MARÍA CELIA; GARCÍA LOMBARDI MERCEDES; BERGADÁ IGNACIO

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

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