Early Career Development Grants

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 children.

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.

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.

Principal investigator: Pratiti Bandopadhayay, MD, PhD, Dana-Farber Cancer Institute
Award: $300,000 over three years
Co-mentors: Rameen Beroukhim, MD, PhD and Charles Stiles, PhD, Dana-Farber Cancer Institute

Twenty-five percent of all medulloblastomas are driven by a gene called MYC. This gene makes the tumors behave aggressively and they are frequently resistant to the current treatments. Dr. Bandopadhayay and Dr. Beroukhim have recently shown that a new group of drugs called BET-bromodomain inhibitors are a promising novel strategy to treat these tumors. They have found that models of medulloblastoma in the laboratory are sensitive to a BET-bromodomain inhibitor, JQ1, which was developed by Dr. James Bradner at Dana-Farber Cancer Institute. However, experience with other novel agents have shown that cancers frequently evolve to become resistant. If the resistance mechanisms are understood, new drugs can be added to overcome resistance. The goals of the project are to characterize the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastoma. The hope is the results will guide development of therapeutic strategies, including use of combination therapies, to improve the efficacy of BET-bromodomain inhibition for the children with MYC-amplified medulloblastoma.

Principal investigator: Marc Remke, MD, Heinrich-Heine University, Dusseldorf, Germany
Award: $300,000 over three years
Mentor: Michael Taylor, MD, PhD, Hospital for Sick Children, Toronto, Canada
Funding Partner: Catching Up with Jack

This project will compare cancer cells and normal cells using tools designed to analyze DNA, RNA and proteins. To this effect, Dr. Remke will use mass spectrometry to profile the proteins of medulloblastoma, the most common malignant brain tumor in children. In addition to protein analysis, he will analyze the RNA of medulloblastoma by sequencing and the DNA by a microarray designed to look at methylation, which is like a switch for whether or not a gene will be turned into RNA. Dr. Remke will then integrate all the data from the protein, RNA and DNA analyses in the hopes that the results will help to inform clinicians about novel treatment strategies and to treat patients according to the aggressiveness of their disease.

Principal investigator: Kyle Walsh, PhD, University of California, San Francisco
Award: $300,000 over three years
Mentor: William Weiss, MD, PhD, UCSF

Very little is known about what causes pediatric ependymomas. The most convincing factors identified to date suggest contributions from genetics and the immune system. By leveraging a large multiethnic patient population drawn from the California Birth Cohort, Dr. Walsh will compare the genomes of approximately 500 children with ependymoma to the genomes of 5,000 cancer-free children to identify genetic risk factors underlying this disease. Special focus will be given to genes involved in the immune response. He will also investigate interactions between genetic factors and potential perinatal risk factors, including birthweight, male sex and early life infections. Dr. Walsh believes that an enhanced understanding of the factors underlying pediatric ependymoma risk, including how genetic variation interacts with immune parameters, can change ependymoma research paradigms and usher in a new generation of studies that target the underlying causes of this disease.