Therapy for the Adolescent-Young Adult Cancer Fibrolamellar Hepatocellular Carcinoma
Abstract
Fibrolamellar hepatocellular carcinoma, FLC, is a usually lethal cancer that is predominantly found in adolescents and young adults with a medium diagnostic age of 21 years. This tumor grows slowly, so it often does not present symptoms until it is fairly large, and often metastasized. Last week we had a patient who had shown no symptoms until he went to his Army physical, where they felt a mass that, when resected, we weighed at more than 8 lbs. Until 3 years ago, little was known about FLC. Was it one disease or many? Was it genetically inherited or environmentally triggered? We reached out to the patient community through social media and recruited patients to work in the lab, and donate tissues and funds for the work. The results demonstrated one major advantage of studying cancers in adolescents and young adults: We found that the genome was very clean. There were no inversions, amplifications, and only one deletion. That deletion resulted in fusing two genes together to form a chimeric fusion of two different genes: a protein called a heat shock protein and a protein that modifies many other molecules, a protein called a kinase. This altered chimeric protein is found only in the tumor cells, and it is been found in every patient tested from over a dozen different institutions. What do these results mean for the patients? First, it means that FLC is only one disease, not a collection of diseases. That facilitates developing diagnostics and therapeutics. Second, it is not genetically inherited. The adjacent liver tissue was normal. Thus, if we can target the aberrant protein and kill those cells, the remaining liver cells are normal and they can regenerate and take over. Third, it gives a very specific target for intervention. We have enough information on the structure of the FLC Chimeric protein that we can use software to not only model its movements, but model which drugs can bind to it. This speeds up drug development. We can order these compounds, test them, and then, with the modeling use medicinal chemistry to optimize these for patient use. In the past 3 years, we have made very rapid progress, and this proposal will leave us, in 2 years, in the position of starting preclinical trials of the compounds. We have two model systems that could be used for these preclinical trials. We already have mice that are growing human FLC tumor, and we have genetically engineered mice to have the FLC chimera -- and this is sufficient to produce tumors. Many of the FLC patients are in the Service, which is possibly the consequence the age distribution of FLC (12-30). It is also found in children of people in the Service. This work shows another major advantage of studying cancers found in people in the age bracket of Service personnel: They are young enough that they have very few background mutations in the normal cells of their body and there tumors have not been festering for many decades, so they do not have many mutations. Thus, it is easier to find the alteration and to design and test therapeutics. This work will have benefits for people of all ages, whether or not they are in the Service.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710290
Entities
People
- Sanford Simon
Organizations
- The Rockefeller University
- United States Army