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PDX可用作晚期胰腺癌理想研究模型

  1. 动物模型
  2. 癌症

来源:生物谷 2015-11-18 17:55

胰腺导管腺癌是一种致死率非常高的恶性癌症,这种疾病具有侵袭性和快速转移的能力,因此胰腺导管腺癌仍然是临床上一种非常难以治疗的疾病。如果能够对胰腺导管腺癌的发病和侵袭转移机制有一个更加深入的了解,将会大大促进治疗药物和治疗手段的开发,但是目前仍然缺少能够代表癌症晚期阶段的理想疾病模型。除此之外,可用于癌症临床前研究的PDX动物模型与病人原位肿瘤之间的分子相似性如何也仍未可知。

                             

 2015年11月18日讯 /生物谷BIOON/ --胰腺导管腺癌是一种致死率非常高的恶性癌症,这种疾病具有侵袭性和快速转移的能力,因此胰腺导管腺癌仍然是临床上一种非常难以治疗的疾病。如果能够对胰腺导管腺癌的发病和侵袭转移机制有一个更加深入的了解,将会大大促进治疗药物和治疗手段的开发,但是目前仍然缺少能够代表癌症晚期阶段的理想疾病模型。除此之外,用于癌症临床前研究的PDX动物模型与病人原位肿瘤之间的分子相似性如何也仍未可知。

 

为了找到转移性胰腺癌进展过程中潜在的驱动分子,来自美国和西班牙的科学家对来自一项尸检项目的原位肿瘤,转移瘤和正常样本(外周血)进行了全外显子测序,同时他们还构建了对应的PDX模型,也进行了测序分析,并将其与病人肿瘤进行了对比。

 
在对来自三位病人的测序数据进行分析之后,研究人员发现每个肿瘤样本中平均存在160个单核苷酸突变,每位病人的大部分突变在原位瘤和转移瘤中都会存在,更为重要的是,这些突变也大部分保留在PDX模型中。
 
基于原位瘤和转移瘤的基因突变率,研究人员提出可能存在克隆进化模式,这种模式中存在的功能性突变会影响一些重要癌基因,比如KRAS ,TP53 ,以及SMAD4,这些癌基因都在肿瘤发生发展和转移过程中起重要作用。
 
这项研究加深了我们对于胰腺肿瘤生物学的理解,同时还表明来源自晚期病人肿瘤组织的PDX模型能够很好地代表该疾病的基因特征,因此PDX模型是非常具有应用前景的可用于开发有效靶向治疗策略的临床前研究平台。(生物谷Bioon.com)
 
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Whole Exome Sequencing of Rapid Autopsy Tumors and Xenograft Models Reveals Possible Driver Mutations Underlying Tumor Progression
 
Tao Xie , Monica Musteanu, Pedro P. Lopez-Casas, David J. Shields, Peter Olson, Paul A. Rejto, Manuel Hidalgo
 
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy due to its propensity to invade and rapidly metastasize and remains very difficult to manage clinically. One major hindrance towards a better understanding of PDAC is the lack of molecular data sets and models representative of end stage disease. Moreover, it remains unclear how molecularly similar patient-derived xenograft (PDX) models are to the primary tumor from which they were derived. To identify potential molecular drivers in metastatic pancreatic cancer progression, we obtained matched primary tumor, metastases and normal (peripheral blood) samples under a rapid autopsy program and performed whole exome sequencing (WES) on tumor as well as normal samples. PDX models were also generated, sequenced and compared to tumors. Across the matched data sets generated for three patients, there were on average approximately 160 single-nucleotide mutations in each sample. The majority of mutations in each patient were shared among the primary and metastatic samples and, importantly, were largely retained in the xenograft models. Based on the mutation prevalence in the primary and metastatic sites, we proposed possible clonal evolution patterns marked by functional mutations affecting cancer genes such as KRAS, TP53 and SMAD4 that may play an important role in tumor initiation, progression and metastasis. These results add to our understanding of pancreatic tumor biology, and demonstrate that PDX models derived from advanced or end-stage likely closely approximate the genetics of the disease in the clinic and thus represent a biologically and clinically relevant pre-clinical platform that may enable the development of effective targeted therapies for PDAC.
 

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