This proposal describes a research plan and training program to develop the principal investigator, Dr. Laura Wood, from junior faculty into an independent physician-scientist. Dr. Wood has performed seminal work in cancer genomics and has completed clinical training in Gastrointestinal, Liver, and Pancreatic Pathology. She was appointed Assistant Professor in July 2013, a tenure-track position with 75% protected time for the proposed studies. Her long-term goal is to develop an independent research program to characterize the molecular events that underlie multistep tumorigenesis in the pancreas. This program will leverage her existing expertise in genomics and pancreatic pathology; however, it will also require additional training in bioinformatics and cell biology in order to independently identify and functionally validate molecular events in pancreatic neoplasms. In order to realize these goals, Dr. Wood has assembled a diverse mentorship team with expertise in cancer genomics, pancreatic pathology, cell biology, and bioinformatics. Her career development plan includes formal coursework as well as seminars, lab meetings, and hands-on training. The proposed research and career development will guide Dr. Wood to a position leading a productive independent research group. Invasive pancreatic cancer arises from non-invasive precancerous lesions that are curable if detected early enough. These precursors include low-grade lesions (which have a low risk of malignant transformation) as well as high-grade lesions (which are equivalent to carcinoma in situ). Early detection of high-grade precursors before their transformation to carcinoma is the key to improving survival of patients with pancreatic neoplasms. In spite of the clinical importance, little is known about the alterations that distinguish low-grade and high-grade precursors in the pancreas. The overall goal of these studies is to determine the somatic mutations that distinguish low-grade from high-grade precursor lesions in the pancreas. After careful pathological review of human tissue samples, we will perform next generation sequencing on matched low-grade and high-grade precursors from patients without associated invasive carcinoma. These studies will allow us to compare the genetic alterations in both types of precursors and identify somatic mutations that are specific to high-grade lesions. In order to distinguish drivers of the progression to high-risk lesions, we will validate the functional effects of these mutations via genetic manipulation in an innovative three-dimensional organoid culture model of human pancreatic neoplasia. Taken together, the proposed studies will help to identify the mutations that causally contribute to the formation of high-risk precursor lesions in the pancreas ? these changes represent the best targets for early detection, treatment, and prevention of pancreatic cancer.

Public Health Relevance

Although pancreatic cancer is a deadly disease with a dismal prognosis, it arises through non- invasive precursor lesions that are curable if detected early enough. The goal of this project is to characterize the molecular alterations that govern the transition from common low-risk precursors to precursors that are at high-risk for progression to pancreatic cancer. The results of these studies could lead to new strategies for early detection of high-risk precursors and prevention of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK107781-01A1
Application #
9179912
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK-C)
Program Officer
Saslowsky, David E
Project Start
2016-07-22
Project End
2021-06-30
Budget Start
2016-07-22
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$158,748
Indirect Cost
$11,759
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Noë, Michaël; Pea, Antonio; Luchini, Claudio et al. (2018) Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. Mod Pathol 31:1532-1538
Felsenstein, Matthäus; Noë, Michaël; Masica, David L et al. (2018) IPMNs with co-occurring invasive cancers: neighbours but not always relatives. Gut 67:1652-1662
Kuboki, Yuko; Fischer, Catherine G; Beleva Guthrie, Violeta et al. (2018) Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. J Pathol :
Noë, Michaël; Rezaee, Neda; Asrani, Kaushal et al. (2018) Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology. Am J Pathol 188:1530-1535
Wood, Laura D; Noë, Michaël; Hackeng, Wenzel et al. (2017) Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas. Virchows Arch 470:391-400
Pea, Antonio; Yu, Jun; Rezaee, Neda et al. (2017) Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas. Ann Surg 266:133-141
Poruk, Katherine E; Blackford, Amanda L; Weiss, Matthew J et al. (2017) Circulating Tumor Cells Expressing Markers of Tumor-Initiating Cells Predict Poor Survival and Cancer Recurrence in Patients with Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 23:2681-2690
Hosoda, Waki; Chianchiano, Peter; Griffin, James F et al. (2017) Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. J Pathol 242:16-23
Luchini, Claudio; Robertson, Scott A; Hong, Seung-Mo et al. (2017) PBRM1 loss is a late event during the development of cholangiocarcinoma. Histopathology 71:375-382
Yachida, Shinichi; Wood, Laura D; Suzuki, Masami et al. (2016) Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma. Cancer Cell 29:229-40