Oncology Research Therapeutic Area, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
J Pharmacol Exp Ther. 2011 Jun;337(3):644-54. doi: 10.1124/jpet.110.178400. Epub 2011 Mar 8.
Ewing's and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents. Recent data suggest that sarcomas may depend on the insulin-like growth factor type 1 (IGF-1) receptor (IGF1R) and/or the insulin receptor (INSR) to drive tumor growth, survival, and resistance to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We evaluated the therapeutic value of ganitumab (AMG 479; C(6472)H(10028)N(1728)O(2020)S(42)), an anti-IGF1R, fully human monoclonal antibody, alone and in combination with rapamycin (mTORC1 inhibitor) in Ewing's (SK-ES-1 and A673) and osteogenic (SJSA-1) sarcoma models. IGF1R was activated by IGF-1 but not by insulin in each sarcoma model. INSR was also activated by IGF-1 in the SJSA-1 and SK-ES-1 models, but not in the A673 model where insulin was the preferred INSR ligand. Ganitumab significantly inhibited the growth of SJSA-1 and SK-ES-1 xenografts; inhibition was associated with decreased IGF1R and Akt phosphorylation, reduced total IGF1R and bromodeoxyuridine detection, and increased caspase-3 expression. Ganitumab inhibited rapamycin-induced IGF1R, Akt, and glycogen synthase kinase-3β hyperphosphorylation in each sarcoma model. However, ganitumab in combination with rapamycin also resulted in a marked increase in INSR expression and activity in the SJSA-1 and A673 models. The in vivo efficacy of ganitumab in the two ganitumab-sensitive models (SJSA-1 and SK-ES-1) was significantly enhanced in combination with rapamycin. Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that INSR signaling is an important mechanism of resistance to IGF1R blockade.
尤文氏肉瘤和骨肉瘤是儿童和青少年癌症死亡的两个主要原因。最近的数据表明，肉瘤可能依赖于胰岛素样生长因子 1 型受体（IGF1R）和/或胰岛素受体（INSR）来驱动肿瘤生长、存活和对哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）抑制剂的耐药性。我们评估了 ganitumab（AMG 479；C(6472)H(10028)N(1728)O(2020)S(42)）的治疗价值，ganitumab 是一种抗 IGF1R 的、完全人源的单克隆抗体，单独使用或与 rapamycin（mTORC1 抑制剂）联合使用，在尤文氏肉瘤（SK-ES-1 和 A673）和骨肉瘤（SJSA-1）肉瘤模型中进行了研究。在每个肉瘤模型中，IGF1R 都被 IGF-1 激活，但不受胰岛素激活。在 SJSA-1 和 SK-ES-1 模型中，INSR 也被 IGF-1 激活，但在 A673 模型中，胰岛素是 INSR 的首选配体。Ganitumab 显著抑制 SJSA-1 和 SK-ES-1 异种移植物的生长；抑制作用与 IGF1R 和 Akt 磷酸化减少、总 IGF1R 和溴脱氧尿苷检测减少以及 caspase-3 表达增加有关。Ganitumab 抑制了每个肉瘤模型中 rapamycin 诱导的 IGF1R、Akt 和糖原合成酶激酶-3β的过度磷酸化。然而，ganitumab 与 rapamycin 联合使用也导致 SJSA-1 和 A673 模型中 INSR 表达和活性的显著增加。Ganitumab 在两种 ganitumab 敏感模型（SJSA-1 和 SK-ES-1）中的体内疗效与 rapamycin 联合使用时显著增强。我们的研究结果支持研究 ganitumab 与 mTORC1 抑制剂联合用于治疗肉瘤，并表明 INSR 信号是 IGF1R 阻断耐药的一个重要机制。
