Mayo Clinic Rochester; University of Pennsylvania

Principal Investigator (contact): Gloria Petersen, PhD
Institution: Mayo Clinic Rochester

Principal Investigator: Kenneth Zaret, PhD
Institution: University of Pennsylvania

Co-Investigators:

  • David Ahlquist, MD, Mayo Clinic Rochester
  • Suresh Chari, MD, Mayo Clinic Rochester
  • Ann Oberg, PhD, Mayo Clinic Rochester
  • Mark Topazian, MD, Mayo Clinic Rochester

Synopsis of Research and Network Resources

Title of the PCDC Project

MAYO CLINIC PROSPECTIVE RESOURCE FOR BIOMARKER VALIDATOIN AND EARLY DETECTION OF PANCREATIC CANCER

Introduction

To achieve the goals of the Pancreatic Cancer Detection Consortium (PCDC), we will leverage Mayo Clinic research registries, biorepositories, and our pancreatic neoplasia practice to develop a resource for collaborative research aimed at improved detection of early stage pancreatic ductal adenocarcinoma (PDAC) and its precursors. Our multidisciplinary team is committed to work with and within the PCDC organization to advance early detection of pancreatic cancer. This project exploits an existing infrastructure and patient registries of pancreatic cancer other pancreatic diseases, plus it will initiate longitudinal collection of blood and pancreatic juice from patients. These samples will be used to validate blood based biomarkers for early detection of pancreatic cancer. We will also validate a panel of biomarkers in pancreatic juice obtained from patients with pancreatic cysts to discriminate those at high risk of developing pancreatic cancer. We will adhere to recommendations for biomarker validation established by the Early Detection Research Network.

Description of the Project

Mayo Clinic researchers (epidemiologists, gastroenterologists, geneticists, biostatisticians) will collaborate with basic researchers and clinical investigators at University of Pennsylvania to develop, validate, and eventually disseminate biomarkers for early detection of pancreatic cancer, focused on high risk groups (high risk family members, patients with premalignant pancreatic cysts, and eventually patients with new onset diabetes).  Significant progress has been made to test and validate blood based biomarkers for pancreatic cancer early detection, and additional work in developing repeated sampling of high risk cohorts of family members and patients with premalignant pancreatic cysts are underway.

Mayo Clinic is an established center of excellence for research in pancreatic conditions, and its ongoing biospecimen resources contain blood samples from ultra-rapidly identified and prospectively enrolled PDAC patients (n=3,092); high risk members in familial pancreatic kindreds (n=2,575); patients with high risk pancreatic conditions (n=1,599); and healthy controls (n=2,791). We will introduce longitudinal biospecimen collection from subjects to validate biomarker performance in various settings. Innovatively identified biomarkers will be evaluated: using cell reprogramming of late stage human PDAC generated cells, the Zaret lab found that, when re-differentiated, underwent early stages of PDAC leading to new candidate biomarkers, including THBS2; the Ahlquist lab identified novel methylated DNA markers for PDAC and high grade dysplasia using unbiased whole methylome sequencing. Our Specific Aims are to:

  1. Construct formal biospecimen sets from DNA, serum, or plasma suitable for PRoBE Phase 2 and 3 biomarker validation studies. We will use existing resources and also prospectively collect blood and pancreatic juice every 1-2 years from patients with pancreatic cysts; we will collect blood every 2 years from existing and prospectively recruited high risk family members >age 50.
     
  2. Validate serum or plasma biomarkers for early detection of pancreatic cancer as directed by the evidence and PCDC consensus in Phase 2 and 3 studies. We will perform a Phase 3 validation of THBS2 and CA19-9 suitable for the primary care setting using PLCO samples. We will perform a Phase 2 validation of THBS2 and CA19-9 suitable for a pancreatology clinic setting of high risk subjects to discriminate PDAC from chronic pancreatitis, cystic neoplasms, or neuroendocrine tumors. We will perform a Phase 2 validation of a panel of methylated DNA markers (including ADCY1, CD1D, BMP3, CLEC11A, TWIST1, ELMO) to discriminate healthy subjects from PDAC patients.
     
  3. Perform a Phase 2 study to validate biomarkers for early detection of pancreatic cancer or high grade dysplasia in patients with pancreatic cysts. We will examine the DNA methylation markers (including ZNF781, PRKCB, CD1D, BMP3, CLEC11A, HOXA, ELMO) that discriminate low grade dysplasia from high grade dysplasia in IPMN. We will validate a panel of these biomarkers in prospectively collected plasma and pancreatic juice of pancreatic cyst patients. Our resources and experience are extensive, from a depth of biobanking experience and biospecimens to epidemiology, gastroenterology, novel biomarker development, and biostatistics expertise relevant to early detection and biomarker validation in PDAC.

Resources for Sharing (e.g., description of cohorts, technologies)

We will develop a virtual biobank linked to a PCDC database of all samples prospectively collected under this funded grant.  Details of existing materials are described in the website referenced below.

Opportunities for Collaboration  

We welcome inquiries about collaborations.  Please see the following website to learn about sample and tissue availability from the Mayo Clinic Biospecimen Resource for Pancreas Research, supported by the Mayo Clinic SPORE in Pancreatic Cancer (CA P50102701): https://www.mayo.edu/research/centers-programs/cancer-research/research-programs/gastrointestinal-cancer-program/mayo-clinic-pancreatic-cancer-spore/core-resources/tissue-core.

We are committed to the principles in “Availability of Research Results: Publications, Intellectual Property Rights, and Sharing Research Resources” outlined in the Administrative Requirements of the 2011 NIH Grants Policy Statement, and reaffirms its support for the concept of making unique research resources and tools we develop available to the scientific community after publication. We agree with NIH in considering that “the sharing of such unique research resources (also called research tools) an important means to enhance the value of NIH-sponsored research.” This is consistent with our commitment to advancing research and discovery worldwide in an effort to understand and improve outcomes for pancreatic cancer. We further agree that all resource sharing agreements must be in full compliance with the Bayh-Dole Act and the Technology Transfer Commercialization Act of 2000.

Datasets will be stripped of identifiers prior to release for sharing, we will follow the data enclave model that make the data available to users only under a data sharing agreement that provides for: (1) a detailed summary of the proposed research project, including a complete list of data requested, (2) a commitment to using the data only for research purposes, (3) a commitment to maintaining confidentiality of the data and not to identify any individual participant, (4) a commitment to securing the data summary statistics using appropriate computer technology, and (5) as commitment to destroying or returning the user data after analyses are completed. In the event of data requests, our preferred method will be to execute a data sharing agreement with the requestor for a limited use dataset as defined by the US Department of Health and Human Services (DHHS). We will also encourage, but not require, collaborative use of the data. Data will be made available approximately 180 days following the publication of the main findings related to that dataset. Requests for data will be handled on a case-by-case basis and we will allocate analyst time throughout the grant period to process the requested data.

While fully supporting the concept of resource sharing, we also recognize that the integrity of biological specimens and the privacy of any participants from whom specimens are obtained must be vigorously protected. Appropriate safeguards are in place and will be utilized to protect the integrity of biospecimens, the privacy of individual research participants, and the intellectual property rights if applicable. All requests for tissue or biospecimens are reviewed by our institutional committees. Upon receiving such approval, we will coordinate to send the biospecimens to the requestor, along with the signed Material Transfer Agreement (MTA) letter that constitutes a legally binding agreement between the institution, the requestor, and his/her institution. A copy of the signed letter is retained by the institution and the PIs.