NORMAL & NEOPLASTIC GROWTH IN THE BRAIN

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.

Grant Number: 5P01CA096832-20
NIH Institute/Center: NIH
Principal Investigator: SUZANNE BAKER