Therapeutic opportunities for pediatric astrocytoma

The long-term goal of this program is aimed at defining the distinctive biology of pediatric astrocytoma and developing novel therapeutics for these tumors that will optimize survival of the affected children and minimize deleterious effects of treatment. Pediatric astrocytomas are the most common overall group of brain cancers in children. While survival in patients with low-grade tumors is very high, the cytotoxic chemo and radiation therapies currently used have high toxicity for the growing brains of children. High-grade astrocytomas are most frequently fatal, even with maximal treatments. Therefore novel therapies are urgently needed.

Project one is aimed at understanding and targeting newly defined oncogenic mutations in Myb transcription factors. Keith Ligon, MD, and Rameen Beroukhim, MD, PhD, will test the hypothesis that truncating MYBL1 drive oncogenesis in vitro and in vivo. Having recently described a MYB-QKI fusion mutation frequently found in low-grade astrocytomas, they will investigate the roles of MYB and QKI in the fusion protein to determine if one or both promote tumorigenesis. Project two is aimed at defining and understanding cooperativity among signaling pathways that drive these distinctive tumors. William Hahn, MD, PhD, and Jean Zhao, PhD, will take a comprehensive genomic approach to pediatric astrocytomas. They will determine whether identified, recurrent mutations in histones, Activin receptor, BRAF and PI3K cooperate with one another.  In addition, they will identify synthetic lethal interactors for genetic mutations observed in these brain tumors in order to understand new signaling components of the oncogenic pathway and identify potential therapeutic targets.  Project three is aimed at targeting the lineage-dependent tumor initiation program common to diverse pediatric astrocytomas. Rosalind Segal, MD, PhD, and Liliana Goumnerova, MD, will investigate the role of the phosphatase Eya1 in Sox2-expressing tumor initiating astrocytoma cells. They will explore the function of Eya1 in regulating Sox2 expression and thereby promoting tumor growth using patient-derived cells and xenografts. Together this collaborative group of investigators will enhance our understanding of pediatric astrocytoma biology and develop novel therapeutic approaches.