T18 IGF1R nuclear localization in pediatric glioblastoma: phenotypic characterization and the use of IGF1R/IR inhibitor OSI906 as a targeted therapy Ayelen Martin1 , Patricia Pennisi1 * 1 Childrens Hospital, Buenos Aires, Argentina

MARTIN AYELEN; PENNISI PATRICIA A

New York

Congreso; Meeting abstracts from the 2020 International Meeting on GH/IGF: actions in the shadow of COVID19; 2020

GH Research Society,

Cancer T18IGF1R nuclear localization in pediatric glioblastoma: phenotypic characterization and the use of IGF1R/IR inhibitor OSI906 as a targeted therapyAyelen Martin , Patricia Pennisi Childrens Hospital, Buenos Aires, ArgentinaThe IGF system of ligands and receptors are known to play an important role in normal and neoplastic growth. Interestingly, in the past few years intact IGF1R has been detectedin the nuclei of human cells, associating its presence with poor prognosis in several tumors. It has been described that IGF1R phosphorylation and subsequent SUMOylation of three conserved Lysins are required for its translocation. Central Nervous System (CNS) tumors are the most frequent solid tumors in pediatric population, being gliomas the most numerous groups. Due to the diference in their evolution and response to treatment, in clinical practice gliomas are divided in low-grade and high-grade tumors. Recently, we have shown that in pediatric gliomas, IGF1R nuclear localization was signifcantly associated with both high grade tumors and increased risk of death. In the present work, we studied the expression of IGFs ligands and receptors in a large cohort of pediatric patients with CNS tumors. We found that, in gliomas, IGF1 expression is higher in high grade tumors. This result, in concordance with previous fndings, suggests that IGF1 signaling through IGF1R may be playing a role in the development of high-grade gliomas. To further explore the role of nuclear IGF1R in these tumors we used U87MG human glioblastoma (GBM) cell line and transfected it with a vector containing wt IGF1R sequence (WtU87 cells) or a mutant form of IGF1R (IGF1R1025X1100X1120X) that avoid receptor´s sumoylation, hence IGF1R is not able to translocate to the nucleus (MutU87 cells). We used these two cell lines for in vitro and in vivo assays and found that in vitro IGF1R nuclear localization increased cell migration, glucose uptake and fatty acid biosynthesis, favoring phospholipid synthesis to TAG accumulation but had no effects on cell proliferation. In vivo, WtU87 cells developed earlier tumors that reachedbigger volumes, suggesting that nuclear IGF1R contributes to a more aggressive phenotype. For children with glioblastomas (GBM), the main therapy after surgical resection isradiotherapy followed by chemotherapy using Temozolomide (TMZ). Even so, the best regimen of treatment still needs to be determined. Herein, we aimed to characterize GBM cell response to IGF1R inhibition by OSI906 alone or in combination with high or low doses of TMZ. We performed in vitro (proliferation assays) and in vivo (sc injection, nude male mice) treatments using OSI906, TMZ or the combination of both drugs, orally administered to the mice.Our results showed that only cells expressing the IGF1R with capacity to translocate to the nucleus were sensitive to OSI906 treatment, and showed synergic tumor growth inhibition in combination with low doses of TMZ .Therefore, IGF1R presence in the nuclei renders GBM cells sensitive to IGF1R targeted therapy alone or in combination with TMZ, both in vivo and in vitro. Taken together our results suggest that in pediatric patients with glioblastomas showing nuclear localization of IGF1R, the use of IGF1R inhibitors, like OSI906 or others, could be useful to reduce TMZ doses and/or avoid radiotherapy specially in young children.