- Michael A. Hollingsworth, Ph.D.
- Surinder Batra, Ph.D.
- David Tuveson, M.D., Ph.D.
- David Lyden, M.D.
- Margaret Mandelson, Ph.D.
Dr. Tony Hollingsworth
Dr. Surinder Batra
Dr. David Tuveson
Dr. David Lyden
Dr. Margaret Mandelson
Principal Investigator (contact): Michael A. Hollingsworth, Ph.D.
Institution: Eppley Institute for Research in Cancer, University of Nebraska Medical Center
Institution: Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center
Site Co-Investigator: Surinder Batra, Ph.D.
Institution: Cold Spring Harbor Laboratory
Site Co-Investigator: David Tuveson, M.D.
Institution: Weill Medical College, Cornell University
Site Co-Investigator: David Lyden, M.D., Ph.D.
Institution: Benaroya Research Institute, Virginia Mason
Site Co-Investigator: Margaret Mandelson, Ph.D.
Synopsis of Research and Network Resources
Title of the PCDC Project
PANCREATIC CANCER DETECTION CONSORTIUM
There are two overall goals of this project.
The first is to assemble a unique and robust collection of early lesions related to pancreatic cancer with matching blood samples, matched sets of tumors and metastasis and control tissues from the same patients, a tissue resource that can be used in the discovery and validation of biomarkers for early disease. We will also assemble a collection of longitudinally obtained blood samples and associated biospecimens from patients at risk for developing pancreatic cancer.
The second goal is to undertake a series of biomarker discovery and prevalidation projects, proposed within this application and by collaborative studies from other investigators that are part of the Pancreatic Cancer Detection Consortium.
Description of the Project
Our project, "Pancreatic Cancer Detection Consortium", is a joint collaboration between our labs at the University of Nebraska Medical Center, Cold Spring Harbor Laboratory, Joan & Sanford I. Weill Medical College at Cornell University, and Benaroya Research Institute at Virginia Mason.
Our laboratories have been considering and studying pancreatic cancer for over 30 years.
For the past 13 years, the Hollingsworth laboratory has conducted 100+ rapid autopsies on pancreatic cancer patients that were seen at our institution. Our autopsy program is unique in that our clinicians have seen and followed virtually all the patients in the program, giving us access to complete longitudinal data on the clinical progression of the cancer, including diagnosis, repeated staging and treatment, and we collect every metastatic site in the patient under rapid conditions that produce tissue that is comparable in quality to that obtained by surgical resection.
The Hollingsworth, Batra and Tuveson groups have previously worked to develop diagnostic tests for pancreatic cancer that build upon the CA19-9 test and incorporate elements of early detection of related structures on mucins.
We have successfully grown organoids from autopsy samples by a program in which fresh tissues are rapidly transported from Omaha to Cold Spring Harbor to establish cultures in collaboration with Dr. Tuveson's group.
Dr. Batra and colleagues have developed a series of novel biomarker tests for mucins in pancreatic cancer that is based upon basic discoveries related to the biology of mucins during pancreatic tumor progression.
Dr. Tuveson and colleagues have developed and employed widely used mouse models of pancreatic cancer for translational research purposes, and recently adapted a procedure for culturing pancreatic cancer organoids from mouse and human tissues for use in pancreatic cancer. For the past few years, Dr. Tuveson has been developing model systems to discover biomarkers of pancreatic cancer including novel methods of evaluating CA19-9, in consultation with Dr. Hollingsworth.
Dr. Lyden has extensive experience functionally characterizing tumor exosomes, and has been successful utilizing the exosome protein content and specific exosome cargo isolated from blood plasma of cancer patients as biomarkers for tumor progression and metastatic dissemination. Dr. Lyden has developed methods for reproducible qualitative and quantitative exosome mass spectrometry
Dr. Mandelson is a cancer epidemiologist with a long-standing focus in etiology and outcomes of pancreas and other gastrointestinal malignancies. She takes a lead role in clinical research and enhancing data and sample collection systems to support studies of pancreas cancer. She previously collaborated with Dr. Hollingsworth and the EDRN by providing data and tissue from “high risk” controls identified as part of a large, population-based case control study of pancreas cancer. Dr. Mandelson has extensive experience in collecting data and creating biorepositories in clinical settings.
Our project proposes the following specific aims:
Specific Aim 1. Establish a comprehensive collection of tissues (fixed, frozen and living as organoids) representing the spectrum of premalignant to malignant and metastatic lesions that occur within individual patients (male and female) obtained at the time of surgery and at autopsy, and develop a collection of longitudinally obtained blood and tissue specimens from patients at risk for pancreatic cancer and that develop pancreatic cancer.
Specific Aim 2. Evaluate 15 novel glycoprotein biomarkers of pancreatic cancer progression in human tissue samples containing cell types that represent the progression of pancreatic cancer from early premalignant lesions to primary and metastatic cancer.
Specific Aim 3. Investigate the levels of 15 novel glycoprotein biomarkers of pancreatic cancer progression in longitudinal samples of serum and plasma from patients that develop pancreatic cancer, and compare these to longitudinal samples of appropriate patients with benign diseases.
Specific Aim 4. Discover cell surface antigens specific to the malignant state by applying phage-display approaches to human pancreatic organoids.
Specific Aim 5. To evaluate and discover exosome-based biomarkers of pancreatic cancer by using an unbiased proteomic analysis of exosomal cargo derived from patients with early stage pancreatic lesions (PanIN3 and early stage tumors) to develop a panel of markers that can accurately predict the progression of these lesions towards pancreatic cancer.
Resources for Sharing (e.g., description of cohorts, technologies)
We will create a repository of organoid cultures isolated from resected primary tumors as well as from rapid autopsy patients (RAP). RAP will enable the generation of organoids from patient-matched, relapsed primary tumors in addition to the full spectrum of metastatic lesions and adjacent PanIN and normal tissue. This renewable resource will allow us to undertake rigorous experimental designs that can be reproduced to obtain unbiased, transparent results and ensure the possibility of independent validation. We will also assemble a cohort of longitudinally-obtained blood samples from patients at risk for pancreatic cancer (genetic predisposition, families with a high penetrance of pancreatic cancer, chronic pancreatitis, recent onset diabetics), which will be available for sharing with high quality collaborative studies.
Opportunities for Collaboration
We plan to enhance our existing resource by 1) collecting additional samples from two centers (UNMC and Virginia Mason); and 2) by developing live cell cultures (organoids) from future surgical resection and autopsy samples obtained in the future
We have established a collaboration with Dr. Gloria Petersen (Mayo) for evaluation of the performance of these biomarker candidates in an independent sample set, which will enable us to establish the robustness, reproducibility and rigor of these potential early detection diagnostics
The investigators will collaborate and share data and resources including biospecimens freely with each other, other members of this consortium, and the NCI; participate in planning and attending workshops and symposia; serve on the Steering Committee and be bound by its decisions; submit information on specimen collection and help to define common data elements (CDEs); and share protocols with the Network members or appropriate collaborators. We are committed to facilitating the discovery, clinical validation, and clinical application of biomarkers through participation in multi-institutional studies. We will provide expertise on cohorts, protocol development, and pathological assessment, and will participate in data quality control, analysis, and interpretation of validation studies as required.