Funded Projects

Phase I/II trial of Dabrafenib, Trametinib, and Hydroxychloroquine (HCQ)

This is a phase I/II trial of dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) + hydroxychloroquine (autophagy inhibitor; HCQ) in BRAF V600E-mutant gliomas and a combination of trametinib + HCQ in BRAF fusion or NF1-driven gliomas in children. The primary aims of this trial are to demonstrate safety and early efficacy of the proposed combinations. Only children whose tumors have failed MEK and/or RAF inhibitors previously will be eligible.

• Award $350,000 over 2 years (2019 – 2021)
• Principal Investigators Dr. Arzu Onar-Thomas, St. Jude Children’s Research Hospital

Phase I/II and Target Validation Study of TAK-580 (MLN2480) for Children with Low-Grade Gliomas and Other RAS/RAF/MEK/ERK Pathway Activated Tumors

TAK-580, a type II inhibitor with excellent CNS penetration and documented activity demonstrated in a number of LGG models, is the focus of this trial. The trial design includes phase 1, 2 and target validation arms, the latter providing the opportunity to verify CNS penetration in patient tumors and evaluate pre- and post-treatment biopsy samples to study pathway inhibition and possible resistance among unresponsive tumors.

• Award $300,000 over 2 years
• Principal Investigators Dr. Karen Wright, Director of Neuro-Oncology, Assistant Professor-Pediatrics, Dana-Farber Cancer Institute, Dr. Daphne Haas-Kogan, Chair-Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, and Sabine Mueller, Associate Professor of Oncology, University of California, San Francisco
• Funding Partners Thea’s Star of Hope, Starry Night Knoxville, Think Fit for Kids

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.

• Award $300,000 over three years
• Principal investigator Pratiti Bandopadhayay, MD, PhD, Dana-Farber Cancer Institute

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

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
• Principal Investigator Stephen C. Mack, PhD, St. Jude’s Children’s Research Hospital

"Project Open DIPG" Study Focused on HDAC Inhibitors

This multi-institutional Project Open DIPG study uses state-of-the-art technology to determine the potency of candidate drugs belonging to the novel class of molecules called HDAC inhibitors. Project Open DIPG is a joint venture by the Pacific Pediatric Neuro-Oncology Consortium, a previous PBTF Opportunity Grant awardee, and the Children’s Brain Tumor Tissue Consortium. The research builds on PNOC’s clinical trial portfolio through biospecimen collection, genomic sequencing, and an experimental animal model systems approach supported by CBTTC. The tissue samples will be added to CBTTC’s biorepository, and data from preclinical drug testing in DIPG tumor samples will be deposited into the CAVATICA platform.

• Award $100,000 over one year with the possibility of renewal
• Principal Investigators Adam Resnick, PhD, Children’s Hospital of Philadelphia (CHOP), Javad Nazarian, PhD, Children’s National Health System, Benjamin Garcia, PhD, University of Pennsylvania
• Funding Partners CJR Memorial Foundation

Central Brain Tumor Registry of the United States Childhood and Adolescents Brain Tumor Report

Brain tumors are the most commonly diagnosed and deadliest form of childhood cancer in children and adolescents 0-19. Yet little is reported on these types of cancer.  The Pediatric Brain Tumor Foundation funded a first-of-its-kind report to provide a statistically relevant and more accurate depiction of the incidence and impact of brain tumors in children and adolescents in the United States. The Central Brain Tumor Registry (CBTRUS) is the largest aggregator of cancer registry data on brain and other CNS tumors in the US and provides the most complete picture of population-based data for children and adolescents diagnosed with a brain tumor.

• Award $64,000 over 1 year (2022)
• Principal Investigators Dr. Quinn Ostrom, Duke Medical Center; Carol Krutchko. Central Brain Tumor Registry of the United States (CBTRUS)

Phase I/II Study of MEK162 for Children with RAS/RAF Pathway Activated Tumors

With the discovery of new targets, the pipeline for PLGA clinical trials is ramping up to be more productive than ever before. The newest PLGA clinical trial, entitled Phase 1/II Study of MEK162 for Children with Ras/Raf Pathway Activated Tumors, opened for recruitment in June 2016. The main purpose of the phase I study is to determine the most effective dosage of the drug for children and adolescents with tumors that have recurred despite standard chemotherapy treatment, and to identify the most common side effects. Spearheaded by Dr. Nathan Robison at the Children’s Hospital of Los Angeles, the trial has already enrolled the first 2 cohorts of patients to evaluate optimal drug dosage and will continue to move forward. The phase II objectives will determine whether MEK162 causes NF1 patents and other tumors thought to be caused by abnormal activation of the Ras/Raf/MAP molecular pathway tumors in the pediatric population to shrink and/or stop growing. The study is projected to span 2 years for patient enrollment and will include 15 different institutions across the country. Update: November 17, 2016 We’re excited to report that at the European Society for Medical Oncology (ESMO) 2016 Congress, held October 7–11 in Copenhagen, Denmark, Dr. Mark Kieran discussed the results of a phase I/II trial of dabrafenib therapy, which demonstrated higher response and lower toxicity in pediatric brain tumors. In this video clip, he discusses how the BRAF inhibitor has significant impact on gliomas in children, with none of the side effects seen in adult melanoma patients and introduces upcoming doublet trials alongside a MEK inhibitor. There are additional findings presented at ESMO 2016 about the effectiveness of targeted combination therapy for children with certain types of low-grade glioma brain tumors. Funded in 2016.

• Principal Investigator Dr. Nathan Robison, Children’s Hospital of Los Angeles
• Funding Partners WhyNotMe? Foundation, Team Jack Foundation

Phase III Study of Prospective Assessment of Vincristine and Vinblastine in Carboplatin-based Chemotherapy

With the collaboration of 3 major medical institutions in Germany, Italy and France, this European partnership has combined forces to create the largest clinical trial for PLGA children ever. Set to open in the second half of 2015, the trial is expected to enroll 3000 patients from 19 different European countries over the course of 5 years. The focus of this trial, titled “Prospective assessment of predictive/prognostic molecular biomarkers in the SIOP-LGG 201X adaptive phase III clinical trial cohort” is to identify the optimum treatment regimen with respect to efficacy, improvement of visual and neurological function, reduction of neurotoxicity as well as treatment duration using a randomized comparison of vinblastine (VBL) versus vincristine (VCR) in a carboplatin-based chemotherapy regimen. An additional novel point of the planned trial is the adaptive design and interim analyses (from year 3 onward), which will allow for the timely investigation of novel targeted agents, once a chemotherapy standard of care ‘winner’ has been established. This trial will establish new precedents for treating children with these two ‘gold standard’ treatments and make room for comparative studies as new targeted drug therapies are developed. PLGA fund at PBTF is a proud sponsor of this unprecedented clinical trial. Funded in 2015.

PNOC 001:Phase II Study of Everolimus for Recurrent or Progressive Low-Grade Glioma in Children

This proposal fills a critical unmet need for a pediatric population with few other therapeutic alternatives and addresses an important problem in PLGG therapy, namely, how to best target dysregulated components within signaling pathways. This study (PNOC001) will elucidate mechanisms by which the most common genetic aberrations in PLGGs influence responses to novel, promising, translatable agents and will enable the next generation of clinical trials in which rational drug combinations are administered to appropriate patients in hypothesis-driven studies. This proposal steps beyond the usual approach of testing agents empirically in response-based trials. It utilizes a novel clinical trial statistical design to establish if specific molecular features are predictive markers of response to a targeted agent and establishes a new paradigm for PLGGs in which tumor tissue is acquired from each child in order to identify biomarkers of response. Funding support for the trial provides for the trial’s implementation and continued patient accrual across PNOC’s 15 member clinical trial consortium. Funding for the trial by PLGA fund at PBTF thus supports the robust accrual into an important clinical trial and enables children from all areas of the country to have access to a novel, directed treatment for PLGGs. Funded in 2013.

• Principal Investigator Susan N. Chi, MD, Dana-Farber Cancer Institute