Project 1: Developing a Diagnostic Test and Therapeutic Agents for Fibrolamellar Hepatocellular Carcinoma
Lay summary
Fibrolamellar hepatocellular carcinoma (FLC) 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 people who undergo surgical resection. The poor prognosis is exacerbated by the lack of existing diagnostic tests and systemic therapy. Our research project is tackling these obstacles.
Sanford M. Simon, Ph.D.
The Rockefeller University, New York
Scientific rationale
We recently demonstrated that there is a single, consistent deletion in one copy of chromosome 19 in people with fibrolamellar hepatocellular carcinoma, resulting in a chimeric gene. This chimera encodes a fusion protein, a constitutively active catalytic subunit of protein kinase A.
We also showed that this fusion protein is sufficient to both trigger FLC and drive FLC. Further, when the protein is withdrawn, the tumors die, demonstrating that they have become addicted to the fusion protein. We also have characterized the pathogenic changes that drive this cancer.
We're now pursuing both therapeutics and diagnostics.
Project aims
This project has two aims:
- Characterize the functional response of fibrolamellar cells to therapeutics. Typically, research groups identify what is changed in a cancer and then target those changes. However, blocking most of the changes that occur in FLC has no effect on the tumor and often damages the healthy liver. Our team's approach is functional precision medicine. We screen for drugs that actually affect the tumor. This approach enabled us to identify two compounds that are being tested in a clinical trial.
- Develop biomarkers for FLC tumor burden. It's difficult to see FLC on scans and particularly hard to detect micrometastases. We need to develop biomarkers for FLC. Doing so will help judge if a potential therapeutic is actually working. And it will help assess if there is a recurrence. Scans have proved too unreliable. They can show masses that are unrelated or miss tumors that are growing.
