Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade.
Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade.
复制标题
分子途径：胰岛素样生长因子-1受体途径阻滞的临床应用和未来方向。
DOI：
10.1158/1078-0432.ccr-14-2518
复制
发表时间：
2015-10-01
期刊：
影响因子：
--
通讯作者：
Lovly CM
中科院分区：
文献类型：
--
作者：
Iams WT;Lovly CM
胰岛素样生长因子-1受体（IGF-1 R）信号通路是一个复杂且受到严格调控的网络，对细胞增殖、生长和存活至关重要。IGF-1 R是许多不同恶性肿瘤患者的潜在治疗靶点。这篇简短的综述总结了针对乳腺癌、肉瘤和非小细胞肺癌（NSCLC）患者的IGF-1 R通路的临床试验结果。讨论的治疗药物包括IGF-1 R单克隆抗体（dalotuzumab、figitumumab、cixutumumab、ganitumab、R1507、AVE 1642）和较新的IGF-1 R通路靶向策略，包括IGF-1和IGF-2单克隆抗体（MEDI-573和BI 836845）和IGF-1 R小分子酪氨酸激酶抑制剂（OSI-906）。在乳腺癌和NSCLC患者中进行的基于几项大型阴性试验的撤回试验与IGF-1 R抑制剂单药治疗在肉瘤患者亚组中的持续成功进行了对比。在这些试验中已经检查了几种不同的生物标志物，并取得了不同程度的成功，包括IGF-1 R及其途径组分的肿瘤表达、血清IGF配体水平、替代途径激活和IGF-1 R途径依赖性的特定分子特征。然而，仍然迫切需要定义预测性生物标志物，以识别可能受益于IGF-1 R定向治疗的患者。正在进行的研究重点是发现这些生物标志物并阐明耐药机制，因为目前正在从床边到实验室对这种治疗靶点进行分析。
The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is a complex and tightly regulated network which is critical for cell proliferation, growth, and survival. IGF-1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF-1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF-1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF-1R pathway targeting strategies including monoclonal antibodies to IGF-1 and IGF-2 (MEDI-573 and BI 836845) and a small molecule tyrosine kinase inhibitor of IGF-1R (OSI-906). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF-1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF-1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF-1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF-1R directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench.