Development and Application of a Porcine Model of Pancreatic Cancer

“猪胰腺癌模型的建立与应用” 项目摘要/摘要 这项研究的长期目标是开发一个平台，在此平台上进行胰腺的实验性治疗 与目前的临床前相比，癌症可以以更有效的方式推进到临床 胰腺癌模型。这个R01应用程序的重点目标是开发一种基因定义的、 免疫活性猪原位胰腺癌模型的建立 关于大体行为、显微镜、肿瘤标志物、遗传序列和转录，并确定 该模型在图像引导手术中的实用价值。肿瘤将通过局部靶向已知的基因来诱导 与胰腺癌(即KRAS、P53、Smad4和CDKN2A)相关，使用以下组合 转基因受试者(NSRRC肿瘤猪)、慢病毒介导的体内基因转移和致瘤导管 细胞植入。一些小鼠模型未能反映人类肿瘤生物学，因为 人类的生理学、解剖学和基因序列。因此，建立猪的动物模型的基本原理是 胰腺癌应该更能预测人类肿瘤生物学和治疗反应，而不是 小鼠模型是这样的，因为猪与人类在基因和表型上有更大的同源性。假说 R01的应用是强制表达相关突变基因或移植致癌 猪胰腺内的胰腺细胞会产生胰腺肿瘤，这个肿瘤模型将 临床上相关和有用的。模型的实用性将通过试剂的对比试验来证明。 用于荧光图像引导手术，这是在小鼠身上不可能进行的实验。这项工作 本R01申请中提出的建议将通过一个由以下成员组成的协作团队来完成 普通/肿瘤外科医生(PI)，一名具有分子设计经验的生物医学工程师，两名 在胰腺癌和基因编辑方面拥有专业知识的分子/细胞生物学家， 管理胰腺癌患者，专门研究胰腺/胃肠道癌症的病理学家，测序和 生物信息学专家和一名生物统计学家。这个项目是创新的，因为没有大型动物模型 胰腺癌是存在的。经过验证的猪胰腺癌模型的影响将增强， 补充和补充来自其他肿瘤模型的临床前数据，并推进实验 以更有效的方式将抗肿瘤疗法推向临床，更少的实验性疗法失败 临床试验。此外，猪胰腺癌模型可以促进胰腺癌的设计和开发 微创导管和能源，用于消融胰腺肿瘤，也用于发展和/或 改进检测、成像、诊断和监测这些肿瘤的技术。

“Development and Application of a Porcine Model of Pancreatic Cancer” PROJECT SUMMARY/ABSTRACT The long-term goal of this research is to develop a platform on which experimental therapies for pancreatic cancer can be advanced to the clinic in a more efficient manner than achievable with current preclinical pancreatic cancer models. The focused objective of this R01 application is to develop a genetically-defined, autochthonous model of pancreatic adenocarcinoma in immunocompetent pigs, provide some validation data with respect to gross behavior, microscopy, tumor markers, genetic sequence, and transcription, and determine the model's utility for image-guided surgery. Tumors will be induced by local targeting of genes known to be associated with pancreatic cancer (namely, KRAS, p53, SMAD4, and CDKN2A), using a combination of transgenic subjects (the NSRRC Onco-pig), lentiviral-mediated in vivo gene transfer, and tumorigenic ductal cell implantation. Some murine models have failed to reflect human tumor biology because of differences in physiology, anatomy, and genetic sequence with humans. So, the rationale to build a porcine model of pancreatic cancer is that it should be more predictive of human tumor biology and response to therapy than murine models are, because swine have greater genetic and phenotypic homology with humans. The hypothesis of this R01 application is that forced expression of relevant mutant genes or transplanted tumorigenic pancreatic cells within the porcine pancreas will produce pancreatic tumors, and that this tumor model will be clinically relevant and useful. The utility of the model will be demonstrated with a comparative trial of reagents for Fluorescence Image-Guided Surgery, in experiments that would not be possible in the mouse. The work proposed in this R01 application will be accomplished through a collaborative team consisting of a general/oncologic surgeon (PI), a biomedical engineer with experience in molecule design, two molecular/cellular biologists with expertise in pancreatic cancer and gene editing, a medical oncologist who manages patients with pancreatic cancer, a pathologist specializing in pancreatic/GI cancers, sequencing and bioinformatics experts, and a biostatistician. This project is innovative because no large animal model of pancreatic cancer exists. The impact of a validated porcine model of pancreatic cancer would be to enhance, complement, and supplement preclinical data from other tumor models, and also to advance experimental anti-tumor therapies to the clinic in a more efficient manner, with fewer experimental therapies failing in clinical trials. In addition, a porcine model of pancreatic cancer could advance the design and development of minimally invasive catheters and energy sources used to ablate pancreatic tumors, and also to develop and/or improve techniques to detect, image, diagnose, and monitor these tumors.