Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies.
Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies.
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癌症中的胰岛素样生长因子 (IGF) 通路靶向：IGF 轴的作用和未来组合研究的机会。
DOI：
10.1007/s11523-017-0514-5
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发表时间：
2017-10
影响因子：
5.4
通讯作者：
Bogenrieder T
中科院分区：
文献类型：
--
作者：
Simpson A;Petnga W;Macaulay VM;Weyer-Czernilofsky U;Bogenrieder T
尽管在癌症中以胰岛素样生长因子(IGF)轴为靶点具有强大的临床前理论基础，但IGF-1受体(IGF-1R)靶向单一疗法的临床研究在很大程度上令人失望，而且任何潜在的成功都受到缺乏有效的预测生物标记物用于患者充实的限制。大量临床前证据表明，IGF轴在癌症中的关键作用是通过一般的增殖/存活机制、与其他有丝分裂信号网络的相互作用以及DNA损伤修复等类别特异性机制来驱动治疗耐药。因此，将IGF靶向药物与标准细胞毒剂、其他靶向药物、内分泌治疗或免疫治疗相结合是一种有吸引力的治疗方法。抗IGF-1R单抗(MAbs)不能抑制IGF配体2(IGF-2)对胰岛素受体异构体A(INSR-A)的激活，从而限制其抗增殖活性。此外，由于IGF-1R酪氨酸激酶抑制剂缺乏特异性，通过经典的代谢INSR-B亚型干扰信号，导致高血糖；这可能会阻止它们在临床有效剂量下使用。相反，IGF-1/IGF-2配体中和单抗通过IGF-1R和INSR-A抑制增殖/抗凋亡信号，而不损害INSR-B的代谢功能。因此，包含这些药物的联合方案可能比以IGF-1R为靶向的联合方案更有效和更容易耐受。在这里，我们回顾了迄今为止IGF靶向治疗的临床前和临床经验，并讨论了未来联合治疗作为克服治疗耐药性的手段的基本原理。
Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF-1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
6.4
作者：
Hoyo, Cathrine;Schildkraut, Joellen M.;Murphy, Susan K.;Chow, Wong-Ho;Vaughan, Thomas L.;Risch, Harvey;Marks, Jeffrey R.;Jirtle, Randy L.;Calingeart, Brian;Mayne, Susan;Fraumeni, Joseph, Jr.;Gammon, Marilie D.
通讯作者：
Gammon, Marilie D.
影响因子：
5.2
作者：
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通讯作者：
Hursting SD
影响因子：
11.5
作者：
Atzori, Francesco;Tabernero, Josep;Baselga, Jose
通讯作者：
Baselga, Jose