Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to the inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the combination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, the growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.
在复发性神经母细胞瘤中观察到RAS/MAPK通路存在激活突变。临床前研究表明，这类肿瘤对RAS/MAPK通路抑制剂（如MEK抑制剂）具有更高的敏感性。MEK抑制剂单药治疗未能产生持久疗效，这表明需要寻找靶向药物的协同组合方案以提升治疗效果。我们先前在RAS突变的横纹肌肉瘤模型中，已证实MEK抑制剂曲美替尼与IGF1R特异性单克隆抗体加尼图单抗具有临床前治疗协同效应。与横纹肌肉瘤细胞类似，神经母细胞瘤细胞对RAS/MAPK通路和IGF1R/AKT/mTOR通路的抑制具有敏感性。我们推测曲美替尼与加尼图单抗联合治疗对RAS突变的神经母细胞瘤可能有效。本研究中，曲美替尼与加尼图单抗在细胞培养中协同抑制神经母细胞瘤细胞增殖并诱导细胞凋亡。在异位和原位移植瘤模型中，联合治疗组观察到肿瘤发生延迟和生存期延长。然而，接受联合治疗的动物仍出现原发性和转移性肿瘤的生长。因此，在将这种联合方案应用于复发性或难治性RAS突变神经母细胞瘤患者之前，仍需开展更多临床前研究。
Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma
肿瘤(癌症)患者之家