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

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

Congreso; XXVIII Congreso Latinoamericano de endocrinología Pediátrica; 2019

Background: CNS tumors are the most frequent solid tumorsin children. In paediatric gliomas, IGF-1R nuclear localization wasassociated with high grade tumours and increased risk of death,contributing to the aggressive phenotype of glioblastoma. 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 treatmentwith OSI906 (IGF1R/IR dual inhibitor) alone or in combinationwith Temozolomide used as a current adjuvant chemotherapyfor paediatric patients.Methods: stably transfected U87Mg glioblastoma cells with 5times basal expression of wild type mature GFP-IGF1R fusion protein(wt-IGF1R, WtU87) or GFP-IGF1R fusion protein mutated inLys1025-1100-1120 to avoid IGF-1R nuclear translocation (m-IGF1R,MutU87) were used for in vitro and in vivo assays. Proliferationassays were carried out for 3 days using complete media(10%FBS) alone or with the addition of IGF-1R/IR inhibitorOSI906 (0.5uM), Temozolomide (TMZ, 40 or 100uM) or the combinationof both. Male nude mice were injected with 1,5e6cells/flank/mice. OSI906 (50mg/kg) and TMZ (400mg/kg) were givenby gavage once daily or as a single dose respectively. Treatmentswere started when tumors reached 150 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 controlcondition. However, cells resumed proliferation after 3 days inculture. 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 proliferationafter 24 h treatment, although the total number of cells wasdecreased compared to control. OSI906 was able to abolish proliferationof WtU87 cells when used alone or in combination withTMZ 40 or 100, having the latter the strongest effect. In vivo studiesshowed similar trends.Conclusion: The capacity of the IGF1R to translocate to thenucleus, renders glioblastoma cells sensitive to the IGF-1R targetedtherapy alone or in combination with TMZ, in vitro and in vivo.These results suggest that the use of IGF1R inhibitors in pediatricpatients showing nuclear localization for this receptor, could beuseful to reduce TMZ doses and or avoid radiotherapy in children.