Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. By using a system biology approach it has been discovered that KDM2B, a Jumonji-domain containing histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogates tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperates with KRASG12D to promote PDAC formation in mouse models in Jumonji-dependent manner. Gain and loss-of-function experiments coupled to genome-wide gene expression and chromatin immunoprecipitation studies revealed that KDM2B drives tumorigenicity by regulating developmental pathways and inducing metabolic reprogramming. Although PDAC is characterized by a well-defined number of genetic lesions, efforts to pharmacologically target those pathways have been unsuccessful. In contrast, the epigenetic networks involved in PDAC are poorly understood at the molecular level and explored as potential therapeutic targets. I generated new genetically engineered mouse models to conditionally ablate and overexpress KDM2B. I propose to conduct a forward genetic screen using the Sleeping Beauty transposon-mediated insertional mutagenesis system to identify oncogenic networks that cooperate with KDM2B in vivo to drive pancreatic cancer development. Given the reversibility of histone methylation and the importance of the Jumonji domain, I propose to use high throughput screening technologies to discover small molecule inhibitors of KDM2B and test their efficacy in vitro and in vivo. This proposal aims to provide further insights into the field of epigenetics of pancreatic cancer, facilitate the understanding of molecular mechanism(s) that drive oncogenesis through identification and testing new molecular targets in vivo, and provide a rich resource of potential cancer driving mutations for cross-comparative analyses with ongoing sequencing efforts in PDAC.

Public Health Relevance

In addition to genetic alterations, epigenetic mechanisms are also central to cancer pathogenesis. Identifying the key epigenetic regulators in pancreatic cancer should point to new and better therapeutic approaches. Given the reversibility of histone modifications small molecule inhibitors of histone demethylase KDM2B may point to new and better therapeutic approaches to treat pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA182662-01
Application #
8623860
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2014-02-17
Project End
2016-01-31
Budget Start
2014-02-17
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$167,480
Indirect Cost
$58,730
Name
George Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052