RNA Therapeutics for Fibrolamellar Hepatocellular Carcinoma

Author

Christoph Neumayer

Date of Award

2024

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Abstract

Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer characterized by a recurrent fusion of the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A (PRKACA). Due to limited efficacy of conventional treatments such as chemotherapy and radiation my work explored new therapeutic options. As DNAJB1::PRKACA is known to initiate tumorigenesis, I reasoned that it would be an ideal target for a therapeutic. However, it was not known if FLC tumors are still dependent on DNAJB1::PRKACA or if cells achieved independence of the initial oncogene. To test if FLC is dependent on the oncokinase I screened short hairpin RNAs (shRNAs) that tile over the fusion junction of the DNAJB1::PRKACA mRNA. I identified a shRNA that achieves strong knockdown of the fusion gene with minimal effect on the wildtype fusion partners.Using this shRNA, I demonstrate that specifically knocking down DNAJB1::PRKACA results in the cell death of FLC cells in vitro and in patient derived xenograft models of FLC in mice. These results show that DNAJB1::PRKACA has a pivotal role in tumor formation, maintenance, and progression and that FLC is oncogenically dependent on DNAJB1::PRKACA. This validates DNAJB1::PRKACA as a therapeutic target.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Neumayer, Christoph, "RNA Therapeutics for Fibrolamellar Hepatocellular Carcinoma" (2024). Student Theses and Dissertations. 769.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/769