Division of Hematology and Oncology, Alfred I. duPont Hospital for Children, Nemours Center for Childhood Cancer Research, Wilmington, Delaware 19803, USA.
Pediatr Blood Cancer. 2010 Jul 15;55(1):67-75. doi: 10.1002/pbc.22479.
The combination of rapamycin and R1507, a fully human IgG1 monoclonal antibody targeting the IGF-1 receptor (IGF-1R), in osteosarcoma xenograft tumors in vivo is evaluated in this report.
Six osteosarcoma xenograft tumor models were evaluated for growth inhibition after monotherapy with R1507, rapamycin, and the combination of both drugs. Phosphorylation of proteins involved in IGF-1R signaling is evaluated at various time points by immunoblotting.
IGF-1R was expressed in five of the six human osteosarcoma tumor lines. Objective responses to R1507 were seen in four of the six tumor lines (OS1, OS2, OS9, and OS17) including one complete response in OS1. IGF-1R protein levels did not predict degree of response to R1507 in the sensitive tumors. However, in one of the two R1507-resistant tumors (OS33), there was a minimal expression of IGF-1R. An increase in AKT phosphorylation was observed in all the osteosarcoma tumors treated with rapamycin. However, phosphorylation of AKT was inhibited when rapamycin was used in combination with R1507. In three of the xenograft tumor lines, there was an improvement in response when R1507 was used in combination with rapamycin.
IGF-1R inhibition by R1507 induced tumor growth delays and improvement in event-free survival in four of six osteosarcoma xenograft tumor lines. R1507 negates increased signaling through AKT in response to mammalian target of rapamycin inhibition, suggesting that the combination is worthy of further evaluation in patients. As R1507 and other IGF-1R inhibitors advance in clinical trials, it will be important to understand biomarkers of response and pathways of resistance.
本报告评估了雷帕霉素（rapamycin）与 R1507（一种针对 IGF-1 受体（IGF-1R）的完全人源 IgG1 单克隆抗体）联合在体内骨肉瘤异种移植瘤中的作用。
在 6 种骨肉瘤异种移植瘤模型中，分别对 R1507、雷帕霉素单药治疗及两药联合治疗的肿瘤生长抑制作用进行了评估。通过免疫印迹法，在不同时间点评估了参与 IGF-1R 信号转导的蛋白的磷酸化情况。
在 6 个人骨肉瘤肿瘤细胞系中，有 5 种表达 IGF-1R。在 6 种肿瘤细胞系中（OS1、OS2、OS9 和 OS17）中的 4 种观察到了 R1507 的客观反应，包括 OS1 中出现 1 例完全缓解。在敏感肿瘤中，IGF-1R 蛋白水平不能预测对 R1507 的反应程度。然而，在 2 种 R1507 耐药肿瘤中的 1 种（OS33）中，IGF-1R 的表达极少。雷帕霉素处理的所有骨肉瘤肿瘤中，AKT 磷酸化均增加。然而，当雷帕霉素与 R1507 联合使用时，AKT 的磷酸化被抑制。在 3 种异种移植瘤中，R1507 与雷帕霉素联合使用时，反应得到改善。
在 6 种骨肉瘤异种移植瘤中，R1507 抑制 IGF-1R 诱导肿瘤生长延迟，并改善无事件生存。R1507 拮抗了哺乳动物雷帕霉素靶蛋白（mTOR）抑制时 AKT 信号的增加，表明该联合方案值得在患者中进一步评估。随着 R1507 和其他 IGF-1R 抑制剂在临床试验中的进展，了解反应的生物标志物和耐药途径将非常重要。
