Therapy for the Adolescent/Young Adult Cancer Fibrolamellar Hepatocellular Carcinoma
Abstract
We are studying fibrolamellar carcinoma (FLC), a usually lethal liver cancer that strikes adolescents and young adults. Our studies reveal a single alteration in the FLC tumor: a deletion in one copy of chromosome 19 that fuses two genes together creating a chimeric protein - a fusion of a heat shock protein (DNAJB1) and a protein kinase (PRKACA). This is the only alteration in the cells and it has been found in 100 percent of FLC patients. Our hypothesis is that blocking or eliminating this DNAJB1-PRKACA chimera kinase can provide the first treatment for this cancer. Our objective is to identify molecules that block this fusion kinase or can be used to target the fusion kinase of degradation. Our rationale is that we know fusion kinases can be blocked via drugs; for example, Gleevac blocks the activity of the BCR-ABL chimera kinase, successfully treating chronic myelogenous leukemia. Our molecular dynamics simulations already predict molecules that should bind to the FLC chimera kinase, but not the native kinase. Finding a molecule that both binds and blocks activity is a high bar. Thus, our second specific aim will look for ways of targeting the FLC chimera kinase for destruction. Targeting the BCR-ABL fusion kinase via a peptide has recently been shown to be an effective way of destroying the kinase.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2018
- Accession Number
- AD1059195
Entities
People
- Eileen J Kennedy
- Sanford M. Simon
Organizations
- The Rockefeller University