Fibrolamellar hepatocellular carcinoma (FLHCC) is an often-lethal disease affecting primarily children and young adults. The poor prognosis stems from both the lack of sensitive non-invasive diagnostic tests and the lack of a targeted systemic therapy. We have recently demonstrated a single, consistent deletion in one copy of chromosome 19 of FLHCC patients that results in a chimeric gene. This encodes a chimeric protein comprised of the amino terminal portion of the heat shock protein DNAJB1 fused to the active catalytic subunit of protein kinase A. This project will determine if this chimera is sufficient for transforming cells. It will then determine the extent of cellular changes upon induction of the chimera and begin to elucidate the pathways and mechanisms for these changes.

Public Health Relevance

Our ability to understand human cancers has been revolutionized the past two decades by the sequencing of the human genome and the ability to introduce altered genes into cells. This project builds upon this by using the study of a pediatric cancer to drive the study of critical genes in human hepatic cells. The project will identify those pathways that should be targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
High Priority, Short Term Project Award (R56)
Project #
5R56CA207929-02
Application #
9319240
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2016-07-20
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Farber, Benjamin A; Lalazar, Gadi; Simon, Elana P et al. (2018) Non coding RNA analysis in fibrolamellar hepatocellular carcinoma. Oncotarget 9:10211-10227
Simon, Sanford (2018) Günter Blobel (1936-?2018). Nature 556:32
Lalazar, Gadi; Simon, Sanford M (2018) Fibrolamellar Carcinoma: Recent Advances and Unresolved Questions on the Molecular Mechanisms. Semin Liver Dis 38:51-59
Graham, Rondell P; Lackner, Carolin; Terracciano, Luigi et al. (2018) Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology 68:1441-1447
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Kastenhuber, Edward R; Lalazar, Gadi; Houlihan, Shauna L et al. (2017) DNAJB1-PRKACA fusion kinase interacts with ?-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci U S A 114:13076-13084