Pediatric Brain Tumor Foundation
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Early Career Development Grants

The Pediatric Brain Tumor Foundation's multi-year Early Career Development grants support rising stars in research, seeding the field for future pediatric brain tumor discovery. Launched in 2014, the Early Career Development program funds talented pediatric brain tumor researchers who are in the first five years of their first faculty position, with the expectation that this funding will facilitate grantees’ transition to becoming fully independent investigators. Previous Early Career Development awards have led to progress in medulloblastoma and neuro-epidemiology research and helped recipients leverage additional research funding to establish their work in the pediatric brain tumor field.

The following projects and their principal investigators were awarded a $300,000 grant following an open Request for Proposals. Proposals were evaluated by a scientific review team on the merit of the principal investigator's mentorship and research environment, productivity to date and career plan, and proposed research project. The funding period for these grants is Sept. 2019 - Sept. 2022.

Maintenance of DIPG Blood-Brain Barrier Integrity by Angiopoietin1

Award: $300,000 over three years
Principal Investigator: Timothy Phoenix, PhD, University of Cincinnati
Co-mentors: Q. Richard Lu, PhD, and Maryam Fouladi, MD, Cincinnati Children’s Hospital Medical Center

In order to enter brain tissue, molecules and cells in the circulation coursing through the central nervous system (CNS) must first cross a specialized biological border in blood vessel walls called the blood-brain barrier (BBB). Drug penetration across the BBB presents a fundamental challenge to effective treatment of many brain tumors, including diffuse intrinsic pontine gliomas (DIPGs), which are unresectable and only temporarily respond to radiation treatment. Dr. Phoenix will characterize the mechanisms that regulate Angiopoietin-1 (Angpt1) expression and function in DIPG and determine the potential of Angpt1-Tie2 inhibition to effect tumor-specific increases in BBB permeability and drug penetration. Findings will open the door for new approaches to manipulating the BBB in DIPG and ultimately better clinical outcomes for the children diagnosed.

Harnessing Viral Mimicry to Target H3K27M-Driven Pediatric Glioma

Award: $300,000 over three years
Principal Investigator: Stephen C. Mack, PhD, St. Jude's Children's Research Hospital
Primary mentor: Donald W. Parsons, MD, PhD, Baylor College of Medicine, Texas Children’s Hospital
Co-mentor: Nada Jabado, MD, PhD, McGill University

Midline high-grade glioma (mHGGs) in children frequently contain a H3 lysine-to-methionine mutation (H3K27M) in histone proteins. Dr. Mack and collaborators showed in prior work that H3K27M-driven mHGGs harbor a global re-patterning of histone modification (H3K27me3 loss and subsequent H3K27ac gain). Moreover, this disrupted epigenome activates the expression of endogenous retroviral (ERV) elements. While the role of ERVs in pediatric glioma is poorly characterized, Dr. Mack showed that ERV expression can be amplified by epigenetic therapies to place cells in a state that mimics a viral infection. In light of these highly unexpected and compelling findings, Dr. Mack proposes to 1) Decode the role of DNA hypomethylation in an Olig2-H3F3A:K27M-PDGFRa Driven Allograft Model and 2) Determine the efficacy of DNA methylome priming of H3K27M glioma cells to immunotherapy.

Identifying Brainstem Glioma Subtypes That Can Be Radiosensitized by ATM Inhibition

Award: $300,000 over three years
Principal Investigator: Zachary Reitman, MD, PhD, Duke University
Co-mentors: David G. Kirsch, MD, PhD, and David M. Ashley, MBBS, PhD, Duke University

Radiation treatment temporarily ameliorates some neurological symptoms caused by diffuse intrinsic pontine glioma (DIPG). However, the tumor invariably recurs. Inhibitors of ATM, a serine/threonine kinase, interfere with DNA damage-sensing and are currently in clinical trials for adults with gliomas and brain metastases. ATM inhibition is known to selectively radiosensitize tumors that have inactivated p53 function.  Dr. Reitman found that brainstem gliomas frequently contain mutations in key components of the p53 pathway and therefore hypothesizes that brainstem gliomas will be susceptible to radiosensitization by ATM inhibition.  Positive results will provide the pre-clinical foundation for clinical trials in children with brainstem gliomas and define genetic biomarkers of response to treatment.