Mechanisms of BRAF Activation in KIAA1549-BRAF Mutant pLGGs
Most pediatric low-grade brain tumors harbor a specific change in their DNA that promotes tumor growth. This DNA change creates a fusion between two genes, the first is a gene (called BRAF) that is already known to promote tumor growth, and the second is a poorly characterized gene. Drugs have been developed which block this fusion gene, but these drugs still have several challenges when they are used to treat patients. The first problem is that many patients are initially resistant to the drugs, which necessitates devising alternative treatment strategies. The second is that many patients have severs dose-limiting toxicity, which requires cessation of treatment. When treatment is stopped, tumors often quickly rebound, which necessitates continuous treatment throughout childhood to forestall tumor progression. This highlights the clear need to develop new ways to treat these tumors. A limitation in developing new treatment strategies is that we don't understand how this DNA change activates the BRAF gene. If we can understand this, then it may lead to new insight into how to target this fusion gene in patients.
Project Goal:
There are two main goals behind this project. The first goal is that I want to understand how this DNA change in the BRAF gene activates BRAF. Our experimental observations, as well as observations from other research groups highlights that our current model of how this gene is activated is incomplete. In these studies I will look at how changes in the structure of this gene fusion influence its activity. A second goal of this project is to find new ways to therapeutically target tumors that have this mutation. We have conducted a survey of all genes in the genome, with the goal of finding genes that are necessary for the survival of cells with this fusion. One of the genes we identified (called DUSP4) was required for cells with this BRAF fusion to survive. In this proposal I will understand why this gene is required for survival, and will try to understand if perturbing this gene is a potential approach to therapeutically target these tumors.
