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以疾病的诊断、治疗、预后、病因为目标;以病人为对象;以群体研究为主要研究方法;以医疗机构为基地的一类医学研究的总称。通过临床研究获得治疗方法的安全性和有效性。在群体中进行药物测试,以期获得剂量、药物作用、不良反应等相关资料,从而对治疗方法进行安全性有效性评价。

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首页 » 临床研究 » Nature:开发出新型成像模型 或揭示胰腺癌治疗新靶点

Nature:开发出新型成像模型 或揭示胰腺癌治疗新靶点

来源:生物谷 2016-06-07 23:53

图片来源:medicalxpress.com

2016年6月8日 讯 /生物谷BIOON/ --胰腺导管腺癌(pancreatic ductal adenocarcinoma)是一种常见的胰腺癌,其具有极大的致死性,患者的5年生存率仅为6%,目前化疗方法并不能够有效治疗胰腺导管腺癌,部分原因是癌细胞对当前的疗法体系具有较高的耐药性。

近日刊登在国际著名杂志Nature上的一项研究报告中,来自加州大学圣地亚哥医学院等机构的研究人员通过研究开发了一种新型模型,该模型不仅可以帮助研究者追踪体内的癌细胞耐药性,还帮助揭示了一种新型的治疗靶点,早期检测结果或许就可提供一种新型策略来遏制胰腺癌细胞生长。

研究者表示,我们开发的这种新型“报道子”小鼠模型可以在活体动物机体中对干细胞信号进行非侵入性的基于图像的追踪;而利用这种策略,研究人员就发现,干细胞基因Musashi (Msi)是胰腺癌进展过程中的关键元件,尤其是Msi基因的表达水平会随着癌症进展而升高,表达Msi的细胞是驱动癌细胞生长、药物耐受性及患者致死的主要原因。

在确定Msi基因可以促进疾病恶化后,研究人员就开发了一种抵御Msi的新一代反义寡核苷酸抑制剂,这些抑制剂可以有效靶向作用并阻断表达Msi的细胞,从而抑制动物模型机体中的肿瘤生长以及病人机体中的癌细胞,病人机体中的癌细胞往往具有较复杂的突变,而且药物耐受性上具有均一性。

代反义寡核苷酸抑制剂是一种合成性的核酸类药物,其可以选择性地结合到来自靶向疾病相关基因的信使RNA上,并使其失活;研究者Reya说道,这项研究或可帮助我们更广泛地研究癌症,通过活体成像技术可以对Msi受体的活性进行可视化分析,因此这些方法就可以用来追踪肿瘤微环境中的癌症干细胞,从而实时观察癌症的生长和转移,并且使其作为一种开发清除耐药性癌细胞的新型药物。

靶向作用原发性肿瘤组织中的Msi基因就可通过抑制胰腺癌生长及改善患者生存率来改变癌症进展的轨迹,本文研究为后期基于Msi拮抗剂开发新型耐药性胰腺癌的新型个体化疗法提供了新的希望和思路。(生物谷Bioon.com)

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Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma

Raymond G. Fox, Nikki K. Lytle, Dawn V. Jaquish, Frederick D. Park, Takahiro Ito, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. Kopp, Marcie Kritzik, Jason K. Sicklick, Maike Sander, Paul M. Grandgenett, Michael A. Hollingsworth, Shinsuke Shibata, Donald Pizzo, Mark A. Valasek, Roman Sasik, Miriam Scadeng, Hideyuki Okano, Youngsoo Kim, A. Robert MacLeod, Andrew M. Lowy & Tannishtha Reya

Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

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