Molecular circuitry of fibrolamellar carcinoma
Fibrolamellar carcinoma is an liver cancer of adolescents and young adults. Currently the only effective treatment is surgery, but this is only possible in a subset of cases. Chemotherapy and targeted therapies have not been successful to date. Important features of this cancer include the presence of an abnormal gene in virtually every patient. This abnormal gene, referred to as DNAJB1-PRKACA, is found in virtually all patients. A key challenge is to understand how DNAJB1-PRKACA affect the growth of cancer cells, and in particular, to determine how important it is for full formed cancers to keep growing. Secondly, it is important to more broadly determine the set of genes required for fibrolamellar carcinomas to survive and grow. This information will guide the development of improved treatments for patients with this disease.
Project Goal:
The goal of this project is to build on recent observations from our group demonstrating that DNAJB1-PRKACA is indeed very important for the growth of fibrolamellar carcinoma. The study will explore in detail what are the associated biochemical mechanisms. We have identified multiple proteins that are controlled by DNAJB1-PRKACA and we have linked several of these to tumor growth and to a unique set of abnormalities in the mitochondria (the cell's energy factories) of fibrolamellar carcinomas. We expect these studies to identify several therapeutic strategies against these tumors.
Project Update 2024:
Fibrolamellar carcinoma (FLC) is a poorly understood liver cancer of adolescents and young adults. Typically diagnosed at an advanced stage, FLC lacks standard therapies and clinical trials with targeted conventional, and immune therapies have shown limited benefit—median survival for advanced FLC is 14 months. FLC has a number of unusual features compared to other cancers. First, virtually all patients have the same genetic change in their tumors, known as a gene fusion. This involves a rearrangement of the DNA that brings together two genes (DNAJB1 and PRKACA) to generate a new abnormal gene. PRKACA is a type of gene called a protein kinase, which normally exists in ‘on’ and ‘off’ states. The fusion gene (DNAJB1-PRKACA) causes PRKACA to always be turned on in FLC tumors. A second feature of these tumors is that they have abnormalities in the mitochondria, which are like factories in the cell that generate energy and building blocks for cell growth and other functions. This ALSF Innovation grant asked the questions: How does DNAJB1-PRKACA cause cancer? What causes the abnormal mitochondria and how does this features affect cancer growth? In the past year, we have been able to demonstrate that DNAJB1-PRKACA controls a biochemical ‘pathway’ that turns and off genes essential for FLC tumors to grow and survive. This pathway also regulates the mitochondrial abnormalities present in these tumors. In the second year of this grant, we will explore how we can use this information to identify promising new treatments for this disease.
