Capurso Gabriele, Fendrich Volker, Rinzivillo Maria, Panzuto Francesco, Bartsch Detlef K, Delle Fave Gianfranco
Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy.
Int J Mol Sci. 2012 Dec 20;14(1):30-45. doi: 10.3390/ijms14010030.
As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents.
随着越来越多关于促进胃肠胰内分泌肿瘤发生和扩散的分子改变的知识被掌握，一些干扰关键生长和血管生成途径的靶向药物已在临床前和临床研究中得到探索。mTOR抑制剂依维莫司和多靶点抗血管生成药物舒尼替尼已被证明有效，因此已被美国食品药品监督管理局（FDA）批准用于治疗胰腺内分泌肿瘤。然而，关于这些肿瘤对靶向药物原发性耐药的数据很少。本综述的目的是阐明联合治疗在克服诱导耐药方面的可能优势，并确定能够预测临床疗效的生物标志物。此外，还讨论了存在强大生物学理论依据且有特定抑制剂的有趣靶点的作用，如Src家族激酶和Hedgehog信号通路。现在需要对细胞系和动物模型进行更多的临床前研究，以在该领域提供更强的临床前背景，以及专门比较一种靶向治疗与另一种靶向治疗或联合不同靶向药物的临床试验。
