Development and Application of a Porcine Model of Pancreatic Cancer

"猪胰腺癌模型的建立与应用" 项目总结/摘要 这项研究的长期目标是开发一个平台， 癌症可以以比目前的临床前治疗方法更有效的方式进展到临床， 胰腺癌模型。该R01申请的重点目标是开发一种遗传上确定的， 免疫活性猪胰腺癌的原位模型，提供一些验证数据 关于大体行为、显微镜检查、肿瘤标志物、基因序列和转录，并确定 该模型用于图像引导手术。肿瘤将通过局部靶向已知的基因来诱导， 与胰腺癌相关的基因（即KRAS、p53、SMAD 4和CDKN 2A）， 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性导管 细胞移植一些小鼠模型由于在肿瘤生物学方面的差异而未能反映人类肿瘤生物学。 生理学，解剖学，和人类的基因序列所以，建立一个猪的 胰腺癌的另一个重要特征是，它应该比胰腺癌更能预测人类肿瘤生物学和对治疗的反应， 鼠模型是，因为猪与人类具有更大的遗传和表型同源性。的假设 该R01应用的一个重要方面是相关突变基因的强制表达或移植的致瘤性 猪胰腺内的胰腺细胞将产生胰腺肿瘤，并且该肿瘤模型将是 临床相关和有用。该模型的实用性将通过试剂的对比试验来证明 荧光图像引导手术，在实验中，这将是不可能的小鼠。工作 本R01申请中提出的建议将通过一个由以下人员组成的协作团队完成： 一般/肿瘤外科医生（PI），具有分子设计经验的生物医学工程师， 具有胰腺癌和基因编辑专业知识的分子/细胞生物学家， 管理胰腺癌患者，专门从事胰腺/GI癌症，测序和 生物信息学专家和生物统计学家。这个项目是创新的，因为没有大型动物模型， 存在胰腺癌。经验证的胰腺癌猪模型的影响将是增强， 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应用于临床， 临床试验此外，猪胰腺癌模型可以促进 用于消融胰腺肿瘤的微创导管和能量源，以及用于发展和/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.