Noncoding RNA Biomarkers for Noninvasive and Early Detection of Pancreatic Cancer

用于胰腺癌非侵入性早期检测的非编码 RNA 生物标志物

• 批准号: 10020380
• 负责人: Ajay Goel
• 金额: $ 71.87万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020380
• 关键词: Adult; Bioinformatics; Biological Assay; Biological Markers; Blood; Body Fluids; Cancer Diagnostics; Cancer Etiology; Cells; Cessation of life; Clinical; Cystic Neoplasm; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic radiologic examination; Disease; Early Diagnosis; Evaluation; Genes; Human; Imaging Device; Individual; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Messenger RNA; Methods; MicroRNAs; Minority; Mucinous; Mucinous Neoplasm; Neoplasms; Non-Invasive Cancer Detection; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Patients; Perception; Plasma; Population; Positron-Emission Tomography; Prospective cohort; Resectable; Resistance; Risk; Sampling; Sensitivity and Specificity; Serum; Small RNA; Solid; Source; Specimen; Standardization; Survival Rate; Talents; Technology; Therapeutic; Tissues; Untranslated RNA; Validation; Vesicle; base; biomarker discovery; biomarker panel; cancer biomarkers; candidate marker; clinically significant; cohort; cost effective; design; differential expression; early detection biomarkers; exosome; genome-wide; high risk; improved; innovation; method development; miRNA expression profiling; microRNA biomarkers; next generation sequencing; novel; novel strategies; outcome forecast; pancreatic neoplasm; premalignant; prognostic; prospective; sample collection; success; transcriptome sequencing; tumorigenesis; whole genome

PROJECT SUMMARY: Pancreatic cancer is the fourth leading cause of adult cancer deaths in the U.S., and will become the second leading cause of cancer-related deaths by 2030. The lack of reliable and cost-effective assays impedes wide-spread pancreatic cancer diagnostics. Clearly, early diagnostic procedures will improve the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), but will require novel methods of development. MicroRNAs (miRNAs) are small noncoding RNAs that are implicated in the tumorigenesis of every human cancer, including PDAC. Importantly, miRNAs are robust and resistant to degradation in tissues and body fluids, making them ideal candidates as non-invasive biomarkers. The recent discovery of cancers that actively excrete specific miRNAs in small vesicles, called “exosomes”, has brought additional enthusiasm to the cancer biomarker arena. Previous attempts to define blood-based miRNA biomarkers that can discriminate between non-invasive, early-stage and late-stage PDAC were insufficiently sensitive or specific because of improperly designed cohorts and the narrow dynamic ranges of technologies used. Furthermore, candidate markers were non-comprehensively selected, studies lacked important controls, and the cohorts were insufficiently powered or validated, or did not represent the average risk population. These factors stifled the discovery of miRNA biomarkers that could identify asymptomatic patients before metastatic disease had developed, or distinguish early stage, radiographically occult PDAC from noninvasive pancreatic precancerous neoplasms (PNs). In this proposal, innovative strategies including Next Generation Sequencing (NGS)-based miRNA-Seq will be applied to the genome-wide and systematic discovery of comprehensive and highly specific blood-based miRNAs by analyzing tissues and matching plasma that discern different stages of invasive PDAC and PN. A novel and powerful new approach is being proposed to identify biomarkers with the highest sensitivity and specificity, which will be validated in a prospective, large, well-characterized samples through the following Specific Aims. Aim #1: Discover candidate cell-free and exosomal-miRNA biomarkers using small RNA-Seq in matched tissue and plasma from patients with PDAC, PNs, pancreatitis and normal pancreas. Aim #2: Develop a cell-free and exosomal-miRNA biomarker panel that distinguishes patients with PDAC from those with PNs or pancreatitis. Aim #3: Clinically validate the optimized panel of non-invasive miRNA biomarkers (identified in Aim #2) in prospective cohorts of patients with PDAC and PNs. This project is innovative as it will use NGS-based miRNA-Sequencing for discovery of cell-free and exosomal miRNA biomarkers in matched tissue and plasma samples, and validate these in multiple, well-characterized cohorts of patients with PNs and PDAC vs. controls. If successful, this proposal will profoundly transform early- detection of pancreatic cancer using a non-invasive, robust and inexpensive clinical assay.

项目总结：胰腺癌是美国成人癌症死亡的第四大原因