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Development and Application of a Porcine Model of Pancreatic Cancer

猪胰腺癌模型的建立及应用

基本信息

批准号：
9891972
负责人：
MARK A CARLSON
金额：
$ 63万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891972
关键词：
Anatomy Animal Model Area Autopsy Behavior Bioinformatics Biomedical Engineering CDKN2A gene Catheters Cells Clinic Clinical Trials Code Complement Data Development Devices Diagnosis Diagnostic Ductal Epithelial Cell Energy-Generating Resources Epithelial Cells Family suidae Female Fluorescence Fluorescent Dyes Gene Transfer Genes Genetic Genetic Transcription Goals Histology Human Image Image-Guided Surgery Immune response Immunocompetent Injections Investigational Therapies KRAS2 gene Label Lentivirus Vector MADH4 gene Magnetic Resonance Imaging Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Measurement Medical Oncologist Methods Microscopic Microscopy Modeling Molecular Monitor Mus Oncogenes Operative Surgical Procedures Pancreas Pancreatic Adenocarcinoma Pathologist Phenotype Physiology Public Health Randomized Reagent Research Sampling Secondary to Slice Study models Surgical Oncologist TP53 gene Techniques Technology Testing Therapeutic Thick Time Transgenic Organisms Transplantation Tumor Biology Tumor Markers Tumor Volume Validation Work anti-cancer therapeutic base cancer therapy clinically relevant comparative trial design exome sequencing experience experimental study fluorescence imaging image guided implantation improved in vivo innovation knock-down lentiviral-mediated male minimally invasive model development mouse model mutant pancreatic cancer model pancreatic cancer patients pancreatic neoplasm pre-clinical response small hairpin RNA subcutaneous transcriptome sequencing tumor tumorigenic vector

项目摘要

“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.

“猪胰腺癌模型的建立及应用” 项目概要/摘要这项研究的长期目标是开发一个平台，在该平台上进行胰腺实验治疗癌症可以比目前的临床前更有效的方式推进到临床胰腺癌模型。该 R01 应用的重点目标是开发一种基因定义的、免疫功能正常的猪胰腺腺癌的本地模型，提供一些验证数据关于总体行为、显微镜检查、肿瘤标志物、基因序列和转录，并确定该模型在图像引导手术中的实用性。肿瘤将通过已知的基因的局部靶向来诱导与胰腺癌（即 KRAS、p53、SMAD4 和 CDKN2A）相关，使用组合转基因受试者（NSRRC Onco-pig）、慢病毒介导的体内基因转移和致瘤性导管细胞植入。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，建立猪模型的基本原理胰腺癌的优点是它应该比人类肿瘤生物学和治疗反应更具预测性小鼠模型是这样的，因为猪与人类有更大的遗传和表型同源性。假设这个R01应用的重点是相关突变基因的强制表达或移植致瘤猪胰腺内的胰腺细胞会产生胰腺肿瘤，并且该肿瘤模型将具有临床相关性和有用性。通过试剂对比试验来证明模型的实用性用于荧光图像引导手术，在小鼠实验中是不可能的。工作本 R01 应用程序中提出的建议将通过一个协作团队来完成，该团队由普通/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，两名具有胰腺癌和基因编辑专业知识的分子/细胞生物学家，一位肿瘤内科医生管理胰腺癌患者，是一位专门研究胰腺/胃肠道癌症、测序和生物信息学专家和生物统计学家。这个项目具有创新性，因为没有大型动物模型胰腺癌存在。经过验证的猪胰腺癌模型的影响将是增强，补充和补充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，失败的实验疗法更少临床试验。此外，猪胰腺癌模型可以促进以下药物的设计和开发：用于消融胰腺肿瘤以及发展和/或改进检测、成像、诊断和监测这些肿瘤的技术。