Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany.
Neuroendocrinology. 2013;97(1):99-112. doi: 10.1159/000336089. Epub 2012 Apr 11.
Current treatment options for neuroendocrine tumors (NET) include somatostatin analogs, interferon-α, peptide receptor-targeted therapy and cytotoxic chemotherapy. Most patients undergo sequential therapies since these drugs are active only in subpopulations of patients and for a limited period of time. There is a need for novel drugs that are capable of amelioration of symptomatology (syndromic control) and/or tumor growth control. A number of diverse signaling pathways are involved in the pathogenesis of NET and tumor growth, thus many potential targets are available for drug targeting. Targeted therapies therefore represent an appropriate developmental therapeutic strategy given the multiplicity of potential targets in NET. These include but are not limited to: inhibitory or activating G protein-coupled receptors, receptor tyrosine kinases, ligands, and intracellular targets such as the mammalian target of rapamycin (mTOR). Numerous drugs that utilize single or multiple targets are currently in clinical development. Recently, two target-directed agents, the multiple tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus, have been approved for the treatment of progressive pancreatic NET. This review provides a broad overview of established and potential molecular targets in NET, summarizes data from phase II and III clinical trials with targeted drugs and outlines future therapeutic directions.
目前，神经内分泌肿瘤（NET）的治疗选择包括生长抑素类似物、干扰素-α、肽受体靶向治疗和细胞毒性化疗。由于这些药物仅在患者亚群中有效且仅在有限的时间内有效，因此大多数患者需要进行序贯治疗。需要新型药物来改善症状（综合征控制）和/或肿瘤生长控制。NET 的发病机制和肿瘤生长涉及多种不同的信号通路，因此有许多潜在的药物靶点可供靶向治疗。鉴于 NET 中存在许多潜在的靶点，因此靶向治疗代表了一种合适的开发治疗策略。这些靶点包括但不限于：抑制性或激活的 G 蛋白偶联受体、受体酪氨酸激酶、配体和细胞内靶点，如哺乳动物雷帕霉素靶蛋白（mTOR）。目前有许多利用单一或多个靶点的药物正在临床开发中。最近，两种靶向药物，多激酶抑制剂舒尼替尼和 mTOR 抑制剂依维莫司，已被批准用于治疗进展性胰腺 NET。本文综述了 NET 中已确立和潜在的分子靶点，总结了靶向药物的 II 期和 III 期临床试验数据，并概述了未来的治疗方向。
