Targeting the IGF-Axis in Cultured Pediatric High-Grade Glioma Cells Inhibits Cell Cycle Progression and Survival

Abstract

Pediatric high-grade gliomas (pHGG) accounts for approximately 8–12% of primary brain tumors in children. Prognosis is poor, with a median survival of 9–15 months. Insulin-like growth factor 1-receptor (IGF-1R) gene amplifications have been identified in high-grade gliomas and may contribute to its highly aggressive phenotype, but the effect of IGF inhibitors on pHGG is yet to be determined. In the present study, we analyzed the response of patient-derived pediatric high-grade glioma cells to a novel IGF-1R inhibitor, the IGF-Trap. Using immunohistochemistry, we found that IGF-1R was localized to both the nucleus and cell membrane in different pHGG patient-derived xenograft (PDX) lines under basal conditions. In response to ligand binding, nuclear levels of the receptor increased, and this was associated with the transcriptional upregulation of both the receptor and cyclin D1, suggesting that IGF-1R could regulate its own expression and cell cycle progression in these cells. Insulin-like growth factor-1 (IGF-1) increased the proliferation of the pHGG cells DIPG13 and SGJ2, and this could be blocked by the addition of the IGF-Trap. The IGF-Trap reduced the colony formation of these cells in an optimal growth medium and impeded the ability of IGF-1 to rescue DIPG13 cells from starvation-induced apoptosis. Collectively, these results implicate the IGF-1 axis in the regulation of cell cycle progression, cellular proliferation, and cell survival in pHGG, and identify the IGF-axis as a target and the IGF-Trap as a potential inhibitor of this axis in pHGG.

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches

“…The IGF-Trap consists of the entire extracellular domain of IGF1R fused with the Fc domain of hIgG1. This IGF-Trap binds to IGF1 and IGF2 in the circulation but not insulin, thereby reducing their bioavailability and inhibiting activation of their cognate receptors and downstream responses [ 129 , 130 , 131 , 132 ]. The therapeutic efficacy of the IGF-Trap has recently been demonstrated in breast carcinoma, high-grade pediatric gliomas, triple-negative breast cancer, and pancreatic ductal adenocarcinoma using in vitro and in vivo models [ 129 , 130 , 131 , 132 , 133 ].…”

“…This IGF-Trap binds to IGF1 and IGF2 in the circulation but not insulin, thereby reducing their bioavailability and inhibiting activation of their cognate receptors and downstream responses [ 129 , 130 , 131 , 132 ]. The therapeutic efficacy of the IGF-Trap has recently been demonstrated in breast carcinoma, high-grade pediatric gliomas, triple-negative breast cancer, and pancreatic ductal adenocarcinoma using in vitro and in vivo models [ 129 , 130 , 131 , 132 , 133 ]. In addition, the IGF-Trap inhibited liver metastasis in mice injected with colon carcinoma MC-38 or lung carcinoma H-59 cells [ 130 ].…”