Funded Projects

Phase II Study of RAD001 for Children with Chemotherapy Hemotherapy

RAD001 is a new oral mTOR inhibitor that has demonstrated excellent inhibition of this pathway at clinically achievable doses. The drug is exceedingly well tolerated and is currently used to reduce the risk of solid organ transplant rejection. This funding supports a formal multi-institutional clinical trial of RAD001 in non-NF1 children with recurrent or progressive LGGs after standard treatment.

Harnessing Viral Mimicry to Target H3K27M-Driven Pediatric Glioma

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 (Early Career Development Grant)
• Principal Investigator Stephen C. Mack, PhD, St. Jude’s Children’s Research Hospital
• Co-mentors Donald W. Parsons, MD, PhD, Baylor College of Medicine, Texas Children’s Hospital and Nada Jabado, MD, PhD, McGill University

Identifying Brainstem Glioma Subtypes That Can Be Radiosensitized by ATM Inhibition

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.

• 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

Resistance to BET-bromodomain inhibitors in MYC-amplified medulloblastoma

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 Pratiti Bandopadhayay, MD, PhD, Dana-Farber Cancer Institute
• Award $300,000 over three years (Early Career Development Grant)
• Co-mentors Rameen Beroukhim, MD, PhD and Charles Stiles, PhD, Dana-Farber Cancer Institute

Unraveling medulloblastoma biology by proteomics

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.

• Award $300,000 over three years (Early Career Development Grant)
• Principal investigator Marc Remke, MD, Heinrich-Heine University, Dusseldorf, Germany
• Funding Partner Catching Up with Jack

Genetic susceptibility to ependymoma and interaction with perinatal risk factors

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.

• Award $300,000 over three years (Early Career Development Grant)
• Principle Investigator Kyle Walsh, PhD, University of California, San Francisco

Prediction of Tumor Progression in Patients with DIPG DMG Using Volumetric Measurements Obtained via Automatic Deep Learning Brain Tumor Segmentation

This project seeks to predict tumor response to treatment and progression in patients with DMG/DIPG by using volumetric measurements obtained via automatic deep learning brain tumor segmentation.  This method intends to create a 3D model to replace the current 2D methods of measurement by using AI methods and widely available MRIs. This project is using AI (an algorithm that Dr. Kazerooni has created) and machine learning for diagnostics, prognosis, and out come, response to treatments. This will run automatically on any scan to give the RAPNO (Response Assessment in Pediatric Neuro-Oncology) info to the clinicians.

• Award  $60,000 over 1 year (2022-2023)
• Principal Investigator Dr. Anahita Fathi Kazerooni, Instructor Center for Data Driven Discovery in Biomedicine at Children’s Hospital of Philadelphia
• Funding Partners Tough2Gether for DIPG/DMG and Elle’s Angels Foundation as part of the DIPG DMG Research Funding Alliance

Low-cost, Rapid and Accurate Molecular Diagnostics for Pediatric High Grade Glioma

This project will optimize a number of wet-lab and computational aspects of an electronic sequencing pipeline which was recently established. By using low-cost DNA sequencers and pHGG focused assays, we will offer patients a more rapid molecular diagnosis (<1 day) to allow prompt enrollment in the most relevant clinical trials and enable practical CSF-based treatment response monitoring over the course of treatment. The project will also reduce the need for lumbar puncture for serial tracking of tumor response in clinic using blood (plasma) samples. Based on the lab’s recently completed prior work showing that tumor DNA shed into spinal fluid can be used for diagnosis and prediction of long-term treatment response. The team will leverage a highly-sensitive amplification technique—LAMP [2]—currently being used in rapid COVID-19 diagnostics (LAMP) along with a novel bioinformatic error correction technique to enable rapid, low-cost, accurate detection of tumor response directly from patient plasma.

• Award $130,000 over 1 year (2022-2023)
• Principal Investigators Dr. Carl Koschmann/Dr. Jack Wadden, University of Michigan Medical Center
• Funding Partners Catching Up With Jack

Defining Essential Genes and Targetable Vulnerabilities in Infant Pineoblastoma

This project combines CRISPRi technology with a Zebra Fish brain tumor model to uncover key druggable pathways for RB1/MYC driven infant Pineoblastoma.

• Award $105,000 over 1 year (2022-2023)
• Principal Investigator Dr. Annie Huang, Sick Kids of Toronto
• Funding Partners Blake Vince Payne Star Fund

Rare but Unforgotten: Preclinical Modeling and Screening of High-risk Pineoblastoma Subgroups

This project is developing preclinical models of high-risk pineoblastoma subgroups and using them to identify therapies designed for the specific biology of these brain tumors.

• Award $100,000 over 1 year (2022-2023)
• Principal Investigators Dr. Paul Northcott, St. Jude Medical Center
• Funding Partners Blake Vince Payne Star Fund