New Investigator Grant Awarded to Lily Keane

DMG, H3K27M mutant, hereafter referred to as simply DMG occurs in a specialized part of the brain called the pons located in the brain stem. This vital organ is responsible for key functions such as heart rate and swallowing. The location of DMG to this area means it is very difficult to remove this tumor. Its aggressive nature means it soon spreads into regions of the brain causing its young patients increased discomfort and limited response to therapy. DMG is characterized by the presence of a mutation called H3K27M. The presence of this mutation impacts on an important complex called the PRC2 complex. This complex has been shown to be important for cell identity i.e., what type of cell will develop. The aim of this project is to understand the role of this important complex, PRC2, in normal development of the pons. What cells rely on its activity for their identity and at what stage of development will be determined by extensive profiling of the pons. Cells that show increased activity of PRC2 will be further profiled on a molecular level. This means that all the DNA in the cell will be examined to see what changes are occurring when PRC2 activity is increased. Key targets that are found to be controlled by PRC2 activity will then be identified and screened for therapeutic effects in DMG tumor cells. This will be carried out using primary tissue from DMG patients and using cells that have been immortalized from DMG patients. We will also try to understand what type of immune cells, microglia, are present in the pons during this critical time period and how they support the growth and expansion of this vulnerable area. We believe by understanding the importance of the PRC2 complex in normal development, we will begin to understand how these processes are deregulated in DMG. This will allow us to identify novel therapeutic targets that may be important for DMG initiation/development. It is our hope that this work will lead to novel treatment options for DMG patients.