Molecular Pathogenesis of Pediatric High-Grade Glioma

Project Summary
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brainstem tumor with an intimate
connection between developmental context and tumor etiology. We and others identified histone H3
K27M mutations in 80% of DIPG and midline high-grade glioma. Multiple lines of evidence from our
group and others show oligodendrocyte progenitor cells (OPCs) as the predominant cell-type expression
signature in DIPG. It remains unclear why the K27M selective advantage is so strongly associated with
midline and hindbrain development, and spatiotemporal differences in the impact of K27M on
oligodendrocyte lineage cell state has not been investigated. We will employ genetically engineered mice
(GEM) in which H3.3 K27M is regulated by the endogenous promoter to study regional and age-
dependent effects of epigenetic dysregulation and tumorigenesis in the physiological context of a full
developing brain. We hypothesize that the cell state in which K27M confers a selective advantage
remains essential for tumor maintenance. Therefore, regulators of cell state may be dependencies for
DIPG, even if their expression is not directly dysregulated by K27M. We will evaluate candidate K27M
targets and regulators of OPC cell state to determine if these can override the effects of K27M in
developing oligodendrocyte lineage and inhibit DIPG growth and/or survival. We will also leverage
multiple GEM models combining relevant DIPG mutations to investigate spatiotemporal selection in early
stages of gliomagenesis and later patterns of glioma invasion in the context of 3-dimensional brain
structure. Other recurrent DIPG mutations are potential therapeutic targets including ACVR1 mutations,
found exclusively in DIPG, and PI3K pathway mutations, found in pediatric high-grade gliomas from all
locations and arising as later events in tumorigenesis. We will use patient-derived DIPG cell lines and
orthotopic xenografts and brain-penetrant selective pathway inhibitors to determine the independent and
cooperative effects of dysregulated ACVR1 and PI3K/mTOR signaling on DIPG tumor growth and to
investigate heterogeneity in therapeutic response. The proposed studies are well-integrated with the
overall programmatic goal to improve understanding and treatment of diffuse intrinsic pontine glioma and
medulloblastoma, which cause devastating mortality and morbidity in children. Integrating themes
pursued in this Project and other Projects in the P01 include investigations of epigenetic dysregulation
(with Project 2), connections between disrupted development and tumorigenesis (with Projects 3 and 4),
and therapeutic vulnerabilities of pediatric brain tumors (with Projects 2 and 4). The Research Cores will
provide expert support in Bioinformatics and Biostatistics (Core B), and Neuropathology (Core C).

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