Non-invasive sampling of DNA markers for pancreatic cancer screening

用于胰腺癌筛查的 DNA 标记物无创采样

• 批准号: 8435334
• 负责人: Yu-Tsueng Liu
• 金额: $ 18.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435334
• 关键词: Bacteria; Bile Acids; Bile fluid; Binding; Biological Markers; Cancer Model; Cancer Patient; Cancerous; Cells; Charge; Codon Nucleotides; DNA; DNA Markers; Deoxyribonucleases; Detection; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Drug Delivery Systems; Duodenum; Early Diagnosis; Environment; Enzymes; Esophageal; Evaluation; Family; Feces; Gastrointestinal tract structure; Genetic; Government; In Vitro; Individual; KRAS2 gene; Knock-out; Left; Magnetism; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Methods; Molecular; Monitor; Mus; Mutation; Nanotechnology; Obesity; Oncogenes; Peptide Hydrolases; Persons; Polymers; Population; Procedures; Recovery; Risk Factors; Sampling; Smoking History; Source; Staging; Surgeon; Survival Rate; Testing; Tube; bile salts; cost effective; design; feeding; follow-up; gel electrophoresis; high risk; improved; in vivo; mortality; nanocoating; nanoparticle; neoplastic cell; novel strategies; pancreatic cancer cells; pancreatic juice; pancreatic neoplasm; particle; screening; tool

DESCRIPTION (provided by applicant): Pancreatic cancer is often a fatal disease with 5-year survival rates of only 1-4%. Early detection can substantially reduce the mortality rate. Mutations of the KRAS oncogene (mainly in codon 12) are present in <90%-95% of cases of pancreatic cancer. KRAS mutations are not specific to pancreatic cancer, but early detection of these mutations in high-risk individuals, combined with the diagnostic follow-up, can save lives. Stool is a very attractive source of cancer-derived DNA that can be used for early screening. However, the hostile environment of the gastrointestinal tract composed of bile salts, DNases, and proteases reduces the chances that pancreatic cancer cells and cancer DNA will survive during the passage. This could be one of the reasons for low sensitivity of detection of pancreatic cancer-related mutations in stool. In order to improve the sensitivity of pancreatic cancer screening in stool samples, we propose to design and test ingestible polymer-coated nano- and microparticles that will be capable of binding and protecting DNA, including pancreatic cancer DNA, until it is excreted in stool. Our specific aims are: (1) Using pancreatic tumor DNA that has KRAS G12D mutation, optimize capture and protection efficiency by the particles in vitro in the presence of bile and pancreatic juice components; (2a) By feeding cancer DNA and the particles to normal mice, test the recovery of KRAS mutations in stool; (2b) Using triple knockout (KRAS-cre-p53) pancreatic cancer model (KPC), test the increase in sensitivity of detection of KRAS mutation in stool. This project will have a high impact on the diagnosis and monitoring of pancreatic cancers. Specifically, the proposed method for non-invasive sampling of cancer DNA can improve feasibility of early screening of pancreatic cancer in high-risk populations, and can be developed into a cost effective early screening and monitoring tool.

描述（由申请人提供）：胰腺癌通常是一种致命的疾病，5年生存率仅为1- 4%。早期发现可以大大降低死亡率。KRAS癌基因突变（主要在密码子12中）存在于<90%-95%的胰腺癌病例中。KRAS突变并非胰腺癌特有，但在高危人群中早期检测这些突变，结合诊断随访，可以挽救生命。粪便是一种非常有吸引力的癌症DNA来源，可用于早期筛查。然而，由胆汁盐、DNA酶和蛋白酶组成的胃肠道的恶劣环境降低了胰腺癌细胞和癌症DNA在传代过程中存活的机会。这可能是粪便中胰腺癌相关突变检测灵敏度低的原因之一。为了提高胰腺癌筛查粪便样本的灵敏度，我们建议设计和测试可摄入的聚合物涂层的纳米和微粒，这些纳米和微粒将能够结合和保护DNA，包括胰腺癌DNA，直到它在粪便中排出。我们的具体目标是：（1）使用具有KRAS G12 D突变的胰腺肿瘤DNA，在胆汁和胰液组分的存在下优化颗粒的体外捕获和保护效率;（2b）使用三重敲除（KRAS-cre-p53）胰腺癌模型（KPC），测试粪便中KRAS突变检测的灵敏度增加。该项目将对胰腺癌的诊断和监测产生重大影响。具体地，所提出的用于癌症DNA的非侵入性采样的方法可以提高在高危人群中早期筛查胰腺癌的可行性，并且可以开发成具有成本效益的早期筛查和监测工具。