Pediatric Brain Tumor Foundation
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Early Career Development Grants

Resistance to BET-bromodomain inhibitors in MYC-amplified medulloblastoma
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.

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

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.

Genetic susceptibility to ependymoma and interaction with perinatal risk factors

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