Student Theses and Dissertations

Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Simon Laboratory


Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. There are no known successful systemic chemotherapies for this disease, and thus, surgery is the only potential path to a cure in patients with FLC. Once the disease has grown or metastasized to a point where surgery is no longer an option, a patient’s chance for survival approaches zero. There is a recurrent genetic deletion in FLC cells, which has been found in almost all FLC tumor samples sequenced to date, but not in normal liver tissue from the same patients. The deletion encompasses ~400kb on chromosome 19 beginning after the first exon of DNAJB1, which codes for a member of the heat shock protein 40 (HSP40/DNAj) family, and ends before the second exon of PRKACA, which codes for the catalytic subunit of protein kinase A (PKAc). The deletion results in a functioning chimeric kinase with exon 1 of DNAJB1 and exons two through ten of PRKACA. In this thesis, I will present my work in two areas with regards to this disease. First, I will present my research working on understanding the pathogenesis of FLC. While we know the oncogene that is responsible for transformation, we do not have a good understanding of how this mutation leads to cancer. I will present proteomic data that shows a unique proteomic and phosphoproteomic signature in FLC and will show that quantification of the PKA system can provide insight into the pathogenesis. In the following chapter, I will present my research on developing the first systemic therapeutic for FLC, by targeting this mutation. I will show how I began by targeting the protein, which proved difficult given the similarities of the mutated protein to the wild-type protein. Then, I will discuss my work on developing an RNA-targeting therapy with antisense oligonucleotides and small interfering RNAs. I will close with a discussion on my thesis work and how I envision future research to continue from what I present here.


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

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