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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.

猪胰腺癌模型的研制与应用