Tumorigenesis of a Pediatric Liver Cancer

The Rockefeller University, New York, NY

Many cancers are the consequence of a change in activity of a particular kind of protein called a kinase. A kinase works by modifying other proteins by adding on to them a particular compound called a phosphate. In some cancers, there is an increase in the amount of the kinase that is made; in other cancers the kinase is trapped in the “on” position and is not properly regulated by the cell. Drug therapies that inhibit kinases that add phosphates to proteins on the amino acid tyrosine, have already been approved by the FDA for treatment of non-small cell lung cancer, renal cell carcinoma, chronic myelogenous leukemia (CML), human epidermal growth factor (Her2+) breast cancer, myelofibrosis, gastrointestinal stromal tumor (GIST), and melanoma. While there are kinases that add phosphates to other amino acids, they have not been studied as potential drivers of cancer. We are studying a specific pediatric cancer that forms in the liver, fibrolamellar hepatocellular carcinoma (FLHCC). We discovered that the only alteration in the tumor cells is the formation of a variant of a kinase which adds phosphates onto the amino acids serine or threonine. We want to understand how such a kinase can cause cancer. If we know how it is working, then we are in a better position to block it without affecting the normal functioning of the cells. With support of The B+ Foundation, we are developing the technology for studying the changes that result from an altered kinase in the cell. This will provide both better understanding of fibrolamellar, provide targets for treatment the disease, but also develop a new way to study the many cancers that are the consequence of an altered kinase in the cell.