Inhibition of IGF1R by IGF1R/IR inhibitor OSI906 as a targeted therapy for glioblastoma: in vitro & in vivo studies

CLEMENT FLORENCIA; GARCÍA LOMBARDI MERCEDES; FERNÁNDEZ MARÍA CELIA; VENARA, MARCELA; BERGADÁ, IGNACIO; MARTIN AYELEN; CASTRO, JULIA FERNANDA; PENNISI, PATRICIA

Viena

Congreso; 58th Annual Meeting for the European Society for Paediatric Endocrinology; 2019

Background: CNS tumours are the most frequent solid tumours in children. In pediatric gliomas, IGF1R nuclear localization was significantly associated with both high grade tumoursand increased risk of death and contributed to the aggressive phenotype of glioblastoma by increasing motility and metabolism oftumour cells rather than increasing its proliferation. For childrenchemotherapy 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 chemotherapyfor pediatric patients.Methods: stably transfected U87Mg glioblastoma cells with5 times basal expression of wild type mature GFP-IGF1R fusionprotein (wt-IGF1R, WtU87) or GFP-IGF1R fusion protein mutated in Lys1025-1100-1120 to avoid IGF1R nuclear translocation(m-IGF1R, MutU87) were used for in vitro and in vivo assays.Proliferation assays were carried out for 3 days using completemedia (10%FBS), or in the presence of IGF1R/IR inhibitor OSI906(0.5uM), Temozolomide (TMZ, 40 or 100uM) or the combination of both treatments. Male nude mice were injected for in vivoexperiments (1,5e6cells/flank/mice). OSI906 (50mg/kg) and TMZ(400mg/kg) were given by gavage once daily or as a single doserespectively. Treatments were started when tumours reached150 mm3.Results: After 24 h of culture, MutU87 cells showed decreasedproliferation when treated with TMZ40 and OSI906; OSI906 hadan additive effect when combined with TMZ40 compared to control condition. However, cells resumed proliferation after 3 daysin culture. On the contrary, treatment with TMZ100 had a stronginhibitory effect, that was not increased by the combination withOSI906. WtU87 treated with TMZ40 or 100 also resumed proliferation after 24 h treatment, although the total number of cellswas decreased compared to control. OSI906 was able to abolishproliferation of WtU87 cells when used alone or in combinationwith TMZ 40 or 100, having the latter the strongest effect. In vivostudies showed similar trends.