Project 1: Developing a Diagnostic Test and Therapeutic Agents for Fibrolamellar Hepatocellular Carcinoma
Fibrolamellar hepatocellular carcinoma
Lay summary
Fibrolamellar hepatocellular carcinoma is an often-lethal disease that affects mainly children and young adults. Fibrolamellar hepatocellular carcinoma usually is diagnosed at an advanced stage because it has vague symptoms. The rate of recurrence is high, even for those who undergo surgical resection. The poor prognosis is exacerbated by the lack of existing diagnostic tests and systemic therapy. This research project is tackling these obstacles.
Sanford M. Simon, Ph.D.
The Rockefeller University, New York
Scientific rationale
Project researchers in the Mayo Clinic Hepatobiliary SPORE recently demonstrated that there is a single, consistent deletion in one copy of chromosome 19 in patients with fibrolamellar hepatocellular carcinoma, resulting in a chimeric gene. This chimera encodes a fusion protein, a constitutively active catalytic subunit of protein kinase A.
This work has been reproduced at many other institutions and the same deletion confirmed in every patient in the absence of any other recurrent alterations in the DNA. These findings demonstrate a clear link to the chimera in the pathogenesis of fibrolamellar hepatocellular carcinoma.
Project aims
The aims of this project are to:
- Develop the first diagnostic tests for fibrolamellar hepatocellular carcinoma. We are developing two kinds of tests: noninvasive blood tests and tests to provide a molecular diagnosis on biopsy samples. Each is being compared, double-blind, against conventional pathology diagnosis, which currently is based on a compatible hematoxylin and eosin stain morphology, plus confirmatory immunostains or FISH testing.
- Screen for compounds that block the activity of the chimera. The goal is to find a compound that selectively blocks the kinase activity of the fibrolamellar hepatocellular carcinoma chimera. Such strategies have proven successful in treating other cancers with dysregulation of specific kinase activity. Our preliminary results using SAXS, NMR and molecular dynamics simulations indicate distinct conformational states between the native PRKACA and the chimeric DNAJB1-PRKACA, encouraging a search for drugs to selectively block the chimera.
