Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary tumor in children, adolescents and young adults. The primary tumor is initiated and driven by a single alteration in the DNA: A deletion of ~400kb that results in a fusion gene between the heat shock co-chaperone DNAJB1 and the catalytic subunit of protein kinase A, PRKACA. If the tumor is limited to the liver, then surgery is the accepted therapy. However, if the tumor has metastasized, there is no accepted therapy. This project will determine how the fusion oncoprotein leads to pathogenesis and will develop therapeutics targeted to the fusion oncoprotein. Pathogenesis is being probed by examining what is different about the fusion oncoprotein that causes changes in the cell. Therapeutics will target the fusion oncoprotein through small molecules to block activity, or small molecules to send it to the proteasome, or small molecules for allosteric inhibition.

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 discovery of specific genes that encode proteins that drive cancers. Many of these, especially in children, are fusions of two different proteins. This project focuses on one specific lethal liver cancer that is driven by such a fusion oncoprotein and studies how that oncoprotein produces the cancer and how to block it and eliminate the tumor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54CA243126-01
Application #
9834349
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Weiwei
Project Start
2019-09-20
Project End
2024-08-31
Budget Start
2019-09-20
Budget End
2024-08-31
Support Year
1
Fiscal Year
2019
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