Ajay Goel, Ph.D.
Daniel Von Hoff, M.D.
Principal Investigator (contact): Ajay Goel, Ph.D.
Institution: Beckman Research Institute, City of Hope Comprehensive Cancer Center
Principal Investigator: Daniel D. Von Hoff, M.D.
Institution: Translational Genomics Research Institute
Synopsis of Research and Network Resources
Title of the PCDC Project
NONCODING RNA BIOMARKERS FOR NONINVASIVE AND EARLY DETECTION OF PANCREATIC CANCER
We will perform a comprehensive and genome-wide evaluation of cell-free and exosomal microRNA biomarkers in serum samples as potential noninvasive biomarkers for the early detection of pancreatic cancers and precancerous lesions. Successful identification of such biomarkers will exert a substantial diagnostic and prognostic impact on the management of this fatal disease.
Description of the Project
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.
Resources for Sharing (e.g., description of cohorts, technologies)
All investigators participating in this project recognize that promising new materials, devices, methods, and technologies may arise during the course of their research. These investigators are aware of, and have agreed to abide by the principles for sharing research resources, as described by the NIH in Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, that govern research data sharing, research tools and resources sharing, materials transfer agreements, and intellectual property management.
We do not propose to generate unique model organisms as a result of the work described in this proposal. We will be willing to share new information generated with other investigators as per NIH guidelines. Otherwise, all of this information either will be available on our institutional websites as unpublished data, or will be published in peer-reviewed journals.