Targeting the mTOR signaling pathway in neuroendocrine tumors.
Targeting the mTOR signaling pathway in neuroendocrine tumors.
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DOI：
10.1007/s11864-014-0294-4
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发表时间：
2014-09
影响因子：
4.3
通讯作者：
Kulke, Matthew
中科院分区：
文献类型：
--
作者：
Chan, Jennifer;Kulke, Matthew
神经内分泌肿瘤（NET）是一组异质性恶性肿瘤，其生物学行为多变但通常是惰性的。分化良好的 NET 可大致分为类癌或胰腺 NET。尽管它们在常规组织学评估中具有相似的特征，但这两种肿瘤亚型具有不同的生物学特性并且对治疗的反应不同，与类癌相比，大多数治疗药物在胰腺 NET 中表现出更高的反应率。直到最近，针对晚期 NET 患者的全身治疗选择仍然有限。然而，随着我们对涉及 NET 发病机制、生长和传播的信号通路的了解不断加深，治疗方案也随之扩大。雷帕霉素 (mTOR) 机制通路的异常信号传导与神经内分泌肿瘤发生有关。此外，在 NET 中观察到 mTOR 通路成分表达的改变，并且与临床结果相关。针对 mTOR 通路已成为治疗晚期 NET 的有效治疗策略。在一项针对晚期胰腺 NET 患者的随机、安慰剂对照研究中，mTOR 抑制剂依维莫司治疗与改善无进展生存期 (PFS) 相关。很大程度上基于这些数据，依维莫司已在美国和欧洲被批准用于治疗晚期胰腺 NET 患者。依维莫司在类癌患者中的活性仍在研究中。在一项针对与类癌综合征相关的晚期类癌患者的随机研究中，与奥曲肽相比，在奥曲肽中添加依维莫司可改善 PFS。然而，结果并未达到基于放射成像集中审查的预先设定的统计显着性水平。一项随机研究的结果正在等待检查依维莫司对胃肠道和肺 NET 无功能患者的疗效。此外，还需要进一步研究以确定原发肿瘤部位或其他临床和分子因素是否会影响对 mTOR 抑制的反应。尽管依维莫司可以减缓肿瘤进展，但很少能实现显着的肿瘤缩小。靶向多个信号通路是一种治疗策略，可以提供更好的肿瘤控制并克服与靶向单一通路相关的耐药机制。正在进行和未来的研究结果将提供有关 mTOR 抑制剂与其他靶向药物（例如 VEGF 通路抑制剂和细胞毒性化疗）联合治疗晚期 NET 的额外益处的重要信息。
Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in our understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved progression-free survival (PFS). Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the prespecified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with nonfunctional gastrointestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.
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胰腺神经内分泌肿瘤中经常改变DAXX/ATRX，MEN1和MTOR途径基因。
DOI：
10.1126/science.1200609
发表时间：
2011-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jiao Y;Shi C;Edil BH;de Wilde RF;Klimstra DS;Maitra A;Schulick RD;Tang LH;Wolfgang CL;Choti MA;Velculescu VE;Diaz LA Jr;Vogelstein B;Kinzler KW;Hruban RH;Papadopoulos N
通讯作者：
Papadopoulos N
影响因子：
5.8
作者：
Fiebrich, Helle-Brit;Siemerink, Ester J. M.;de Vries, Elisabeth G. E.
通讯作者：
de Vries, Elisabeth G. E.
影响因子：
45.3
作者：
Kouvaraki, MA;Ajani, JA;Yao, JG
通讯作者：
Yao, JG
影响因子：
8.8
作者：
Duran, I.;Kortmansky, J.;Siu, L. L.
通讯作者：
Siu, L. L.
影响因子：
45.3
作者：
Kulke, Matthew H.;Siu, Lillian L.;Yao, James C.
通讯作者：
Yao, James C.