Grant: Project Grant

Pediatric high-grade gliomas are rare and always lethal brain cancers. Unlike other malignancies, they harbor few mutations in genes. Only some tumors have mutations in established cancer driver genes. These results led us to hypothesize that the biology of pediatric high-grade gliomas may be driven in large part by epigenetic events. Specifically, we hypothesize that DNA regions that that act as switches for genes could be aberrantly turned on or off to maximize the ability of the tumor to grow. These switches are controlled by proteins called transcription factors. In this application, we propose to investigate the role of control regions (the switches) in determining gene expression and functional properties of malignant cells. Our preliminary data indicate that different switches are turned on when the tumor recurs after treatment, and that this phenomenon may contribute to the emergence of properties that are typical of the tumor at relapse. Because tumors at diagnosis and relapse are so different, our data highlight the importance of specifically studying relapse samples, which are the entities that ultimately kill patients. Our studies will focus on rare pairs of diagnostic and relapse samples from the same patients, as well as on patient-derived models for functional validation. In the proposed studies, we will identify the transcription factors that are turning these switches on or off. The ultimate goal of our proposal is to understand how pediatric high-grade gliomas originate and evolve, and to identify strategies to prevent relapses through new and targeted therapeutic interventions.