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: 8227305
• 负责人: Dmitri Simberg
• 金额: $ 16.1万
• 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/8227305
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Early detection of pancreatic cancer can substantially reduce the mortality rate. We propose to design and test a novel approach to improve the sensitivity of detection of pancreatic cancer mutations in stool. This project will have a high impact on the diagnosis and monitoring of pancreatic cancers, especially for screening in high-risk populations.

描述（由申请人提供）：胰腺癌通常是一种致命疾病，5 年生存率仅为 1-4%。早期发现可以大大降低死亡率。 <90%-95% 的胰腺癌病例中存在 KRAS 癌基因突变（主要是密码子 12）。 KRAS 突变并非胰腺癌特有的，但在高危个体中及早发现这些突变并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。为了提高粪便样本中胰腺癌筛查的灵敏度，我们建议设计和测试可摄入的聚合物涂层纳米颗粒和微米颗粒，这些颗粒将能够结合和保护DNA，包括胰腺癌DNA，直到其从粪便中排出。我们的具体目标是：（1）利用具有KRAS G12D突变的胰腺肿瘤DNA，优化颗粒在体外胆汁和胰液成分存在下的捕获和保护效率； (2a) 通过将癌症DNA和颗粒喂给正常小鼠，测试粪便中KRAS突变的恢复情况； (2b) 使用三重敲除 (KRAS-cre-p53) 胰腺癌模型 (KPC)，测试粪便中 KRAS 突变检测灵敏度的增加。该项目将对胰腺癌的诊断和监测产生重大影响。具体来说，所提出的癌症DNA非侵入性采样方法可以提高高危人群胰腺癌早期筛查的可行性，并可以发展成为一种具有成本效益的早期筛查和监测工具。 公共卫生相关性：早期发现胰腺癌可以大大降低死亡率。我们建议设计并测试一种新方法来提高粪便中胰腺癌突变检测的灵敏度。该项目将对胰腺癌的诊断和监测，特别是高危人群的筛查产生重大影响。