Research Project
10270671
Overall Program Summary Brain tumors are the most common pediatric solid malignancies, and the leading cause of cancer-related death in children. The long-term goal of this Program Project is to improve understanding and treatment of diffuse intrinsic pontine glioma (DIPG) and medulloblastoma (MB), which cause devastating mortality and morbidity in children. Over the last funding period, P01 investigators Baker, Roussel and Gilbertson demonstrated important contributions of epigenetic dysregulation in DIPG and MB, a role for pediatric brain tumor mutations in stress response, and therapeutic vulnerabilities in MB subtypes. P01 Investigator Northcott joins as a new Project leader with a proposal based on the discovery of a new MB cancer predisposition gene. This highly interactive team proposes an integrated series of experiments to leverage recent progress and the most advanced techniques to investigate aberrant cell fate/cell state regulation, to determine the contribution of epigenome, transcriptome and proteome dysregulation to disrupted development and tumorigenesis, and to identify developmental and epigenetic functional dependencies and test therapeutic vulnerabilities of pediatric hindbrain tumors. In Project 1, S Baker is focused on the contribution of H3K27M mutations in disrupted development, tumor initiation and spatiotemporal selectivity of tumorigenesis, and how cooperative contributions of ACVR1 and PI3K/mTOR pathways influence heterogeneity of therapeutic response to selective inhibitors. In Project 2, M Roussel investigates the role of the methyltransferase SMYD3, and tests drug combinations that enhance efficacy of methyltransferase inhibitors in the Group 3 MB subtype. In Project 3, P Northcott evaluates how loss of function in ELP1 drives MB predisposition, perturbs regulation of translation elongation, and cooperates with other mutations in the SHH-MB subtype. In Project 4, R Gilbertson investigates how DDX3X mutations disrupt cell fate decisions, transcription and translation regulation, and investigates novel therapies to exploit the defective blood-brain-barrier in WNT-MB. All four projects rely on the outstanding expertise in Core B, where all next-generation sequence data will be analyzed including integrated cross-comparison of data from multiple projects, and rigorous biostatistical approaches will be applied for experimental design and interpretation. Core C is integral to all projects and will provide expert neuropathological review of all tumor models studied in the program to assess their similarity and relevance to primary human disease and will assist with phenotype analyses and optimizing immunohistochemical analyses. The collective efforts of the Program will impact our understanding of disease pathogenesis of DIPG and MB, extend beyond pediatric hindbrain tumors, to enhance understanding of how aberrant regulation of the epigenome, transcriptome and proteome disrupt normal development and contribute to cancer. Our success is guaranteed by our strong track record of productive collaborations, the unique resources and the outstanding Cores to facilitate the acquisition, exchange, and integration of data.
