Aristizabal Prada E T, Auernhammer C J
Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
Department of Internal Medicine IVCampus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
Endocr Connect. 2018 Jan;7(1):R1-R25. doi: 10.1530/EC-17-0286. Epub 2017 Nov 16.
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.
目前，胃肠胰（GEP）系统晚期神经内分泌肿瘤（NETs）的分子靶向治疗包括使用雷帕霉素哺乳动物靶点（mTOR）抑制剂依维莫司和多酪氨酸激酶抑制剂舒尼替尼的获批疗法。然而，由于肿瘤耐药性，这些治疗策略的临床疗效受到客观缓解率低和无进展生存期有限的限制。因此，需要针对GEP系统NETs的分子靶向治疗的进一步新策略。本文综述了GEP系统NETs的临床前研究模型和信号通路。讨论了关于GEP系统NETs分子靶向治疗假定新靶点的临床前和早期临床数据，包括PI3K、Akt、mTORC1/mTORC2、GSK3、c-Met、Ras-Raf-MEK-ERK、胚胎发育途径（Hedgehog、Notch、Wnt/β-连环蛋白、TGF-β信号传导和SMAD蛋白）、肿瘤抑制因子和细胞周期调节因子（p53、细胞周期蛋白依赖性激酶（CDKs）CDK4/6、CDK抑制剂p27、视网膜母细胞瘤蛋白（Rb））、热休克蛋白HSP90、极光激酶、Src激酶家族、粘着斑激酶以及组蛋白去乙酰化酶抑制剂的表观遗传调控。
