Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611, USA.
Expert Opin Investig Drugs. 2013 Jun;22(6):715-22. doi: 10.1517/13543784.2013.787066. Epub 2013 Apr 2.
Because of the central role of the mammalian target of rapamycin (mTOR) pathway in the control and distribution of signals essential for mRNA translation of mitogenic genes and generation of oncogenic proteins, effective targeting of mTOR remains a major goal in medical oncology.
This article summarizes preclinical and clinical studies relating to the next generation of mTOR inhibitors. While rapalogs have shown activity in the treatment of breast, renal and neuroendocrine tumors, these agents do not block mTORC2, one of the two major protein complexes in which mTOR participates. In addition, there is emerging evidence that these agents only partially block mTORC1, underscoring the need for more effective mTOR inhibitors. In recent years, catalytic mTOR inhibitors have been developed, which block both mTORC1 and mTORC2. Such inhibitors show generally better activity in preclinical models than rapalogs and some of them have been or are in clinical trials in humans.
It is anticipated that with the continuous expansion of work in this research field, the therapeutic potential of targeting the mTOR pathway for the treatment of several malignancies will reach a maximum point in the next few years and may ultimately change the way we treat several malignant tumors.
由于哺乳动物雷帕霉素靶蛋白（mTOR）途径在控制和分配对于有丝分裂基因 mRNA 翻译和致癌蛋白产生至关重要的信号方面起着核心作用，因此有效靶向 mTOR 仍然是医学肿瘤学的主要目标。
本文总结了与下一代 mTOR 抑制剂相关的临床前和临床研究。虽然雷帕霉素类似物在治疗乳腺癌、肾癌和神经内分泌肿瘤方面显示出活性，但这些药物不能阻断 mTORC2，mTOR 参与的两个主要蛋白质复合物之一。此外，有新的证据表明，这些药物仅部分阻断 mTORC1，这突显了需要更有效的 mTOR 抑制剂。近年来，已经开发出催化 mTOR 抑制剂，可阻断 mTORC1 和 mTORC2。与雷帕霉素相比，这类抑制剂在临床前模型中通常显示出更好的活性，其中一些已在或正在进行人类临床试验。
预计随着该研究领域工作的不断扩展，靶向 mTOR 途径治疗几种恶性肿瘤的治疗潜力将在未来几年内达到最大值，并可能最终改变我们治疗几种恶性肿瘤的方式。
