The past decade has witnessed unprecedented progress in our understanding of the genetic changes underlying human pancreatic cancer. Led by a long series of important contributions by Program investigators, the genetic and epigenetic basis for pancreatic cancer has slowly been unraveled, with over 30 genetic loci now recognized to undergo mutation in this disease, and characteristic changes in gene expression reported for an even larger number of coding genes and non-coding microRNAs. However, the functional contribution of these mutations to the pancreatic cancer phenotype remains largely uninvestigated. The central Aim of this Program Project Grant is to narrow the gap between genetic and functional data, by determining the functional significance of molecular alterations identified in human pancreatic cancer. This functional annotation will be pursued by examining the impact of candidate dominant and recessive mutations, as well as characteristic changes in microRNA expression, using novel cell-, zebrafish- and mouse-based assays developed by members of our group. Four projects will be pursued: Project 1: Functional annotation of human pancreatic cancer genes in a zebrafish system (Leach);Project 2: Discovery and evaluation of prioritized mutations in human pancreatic cancer (Kern);Project 3: The Hippo signaling pathway in pancreatic cancer (Maitra);and Project 4: Functional evaluation of microRNAs in pancreatic neoplasia (Mendell). These projects will be supported by three shared Cores: Core A: Cellular and Transgenic Phenotyping Core (Huso);Core B: Zebrafish Core (Parsons), and Core C: Administrative Core (Leach). The investigators pursuing these projects are all leaders in the field of pancreatic cancer research, and have an outstanding track record of synergistic interaction. The Program also leverages many already existing resources available at Johns Hopkins, including aspects of the NCI Gl SPORE grant, core resources provided by the Johns Hopkins Comprehensive Cancer Center, and the independently funded Pancreatic Cancer Genome Project. Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications.

Public Health Relevance

Pancreatic cancer represents one of the most deadly human malignancies, with five year survival rates of less than 5% and no change in this figure over the past four decades. By determining the genetic basis for this disease, our program will generate clinically relevant information that is likely to directly impact on strategies for chemoprevention, early detection and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA134292-05
Application #
8464653
Study Section
Special Emphasis Panel (ZCA1-GRB-S (J1))
Program Officer
Mietz, Judy
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,389,750
Indirect Cost
$534,792
Name
Johns Hopkins University
Department
Surgery
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Rakheja, Dinesh; Chen, Kenneth S; Liu, Yangjian et al. (2014) Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat Commun 2:4802
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