Funded Projects

Novel Therapeutic Target for KIAA1549-BRAF-Rearranged Pediatric Gliomas

Pediatric low-grade gliomas (pLGGs) are the most common group of pediatric brain tumors and associated with significant morbidities. The most frequent driver alteration in pLGGs is KIAA1549-BRAF rearrangements. While MAPK pathway inhibitors have shown promise in targeting BRAF activation, they are not curative and many pediatric low-grade gliomas have primary resistance to these inhibitors. Through previous research funding, Drs. Pratiti (Mimi) Bandopadhayay's and Rameen Beroukhim’s research team at Dana-Farber Cancer Institute have identified a specific protein complex that is highly and specifically dependent on cells expressing KIAA1549-BRAF, with the potential to be a therapeutic target for KIAA1549-BRAF-rearranged pediatric gliomas. With this grant’s new funding, the team plans to test the protein complex’s impact on this type of tumor and investigate the combined treatment of MAPK inhibitors and complex suppression to determine if it results in sustained responses in pediatric glioma models.

• Award $750,000 over 2 years
• Principal Investigators Pratiti (Mimi) Bandopadhayay, MBBS PhD, and Rameen Beroukhim, MD PhD, Dana-Farber Cancer Institute
• Funding Partners Catching Up With Jack; Hope for Kids Fund; Jacks Drive 55 Foundation through PBTF's PLGA Fund

Rebound and Resistance of Pediatric Low-Grade Gliomas to MAPK Pathway Inhibitors (Expanded Funding)

This grant builds on the successful results of the Dana-Farber Cancer Institute research team’s work on optimizing targeted inhibition to overcome resistance and/or rebound growth in the treatment of pediatric low-grade gliomas (pLGGs) and their study of the biological factors and cellular changes that contribute to some pLGGs’ resistance to treatment and subsequent regrowth. In addition to the Pediatric Brain Tumor Foundation's expanded funding, the results generated by our early seed funding have led Dana-Farber Cancer Institute’s research team to secure a grant from the Department of Defense, opening the door to investigating other important aspects of rebound and resistance.

• Award $300,000 over 2 years
• Principal Investigators Pratiti (Mimi) Bandopadhayay, MBBS PhD, and Rameen Beroukhim, MD PhD, Dana-Farber Cancer Institute
• Funding Partner Jacks Drive 55 Foundation through PBTF's PLGA Fund

Targeting Cancer Stem Cells in Pediatric Fibrillary Astroctyoma

The ultimate goal of this proposal by principal investigators Dr. David H. Rowitch, Dr. C. David James, and Dr. Graeme Hodgson, Ph.D. of the University of California, San Francisco is to change the landscape of pediatric grade II glioma (fibrillary astrocytoma) research by investigating the biological regulation of cancer stem cells. The three specific aims of this program are as follows: 1) investigate the function of OLIG2-positive stem cells in pediatric low-grade glioma, 2) develop novel mouse orthotopic models of low-grade glioma, and 3) identity genes that cause diffuse low-grade astrocytomas (DLGAs) and test the efficacy of small inhibitory nucleic acids (siNA) that target these genes in preclinical models of DLGAs.

• Principal Investigators Dr. David H. Rowitch, Dr. C. David James, and Dr. Graeme Hodgson, Ph.D. of the University of California, San Francisco

Xenograft Mouse Models of Childhood Low-Grade Glioma

The goal of this project, led by principal investigator Xiao-Nan Li, MD, PhD, Texas Children’s Hospital-Baylor College of Medicine, is to develop and characterize a panel of primary tumor-based orthotopic xenograft mouse models of pediatric low-grade glioma for broad distribution and use in understanding the biology and testing of novel therapies. Using surgical protocols that have successfully achieved greater than 70% (20 models from 28 specimens) tumor take rate in malignant pediatric brain tumors, researchers aim to develop 4-5 transplantable orthotopic xenograft models through direct implantation of 20-25 fresh surgical specimens of low grade gliomas into anatomically matched locations in mouse brains. Detailed characterization of the xenograft tumors will be performed to make sure they faithfully replicate the biology of the original patient’s tumor, and to identify all genetic abnormalities. The research team will also examine if cancer stem cells play a role in determining the xenograft forming capabilities by correlating cancer stem cell frequencies in patient tumors with their tumor take rate.

• Principal Investigator Xiao-Nan Li, MD, PhD, Texas Children’s Hospital-Baylor College of Medicine

Using Human Neural Stem Cells to Create Genetically Accurate Models of PLGG, Developing PLGG Models Using Patient-Derived Tumor Tissue, Dual mTOR/NOTCH inhibition as a Therapeutic Strategy for PLGG

This award is made up of three distinct projects at Johns Hopkins Medical Center with Dr. Eric Raabe, Dr. Charles Eberhart, and Dr. Fausto Rodriguez. Using human neural stem cells to create genetically accurate models of LGG: Researchers have shown that they can take normal human brain cells and introduce into these cells the genetic changes that they find in LGG. Although they can model three of the six subtypes of LGG, the cells do not grow for enough time to allow researchers to use them for drug screen. Models of pediatric LGG which grow robustly and allow the study of tumor biology and drug testing are desperately needed. In prior work from multiple groups, including the research team’s own, tumor-derived cells have stop growing over time, limiting researchers’ ability to study them. Recent studies suggest that in addition to BRAF, other signaling pathways are operational in LGG and other low-grade gliomas in children.

• Award three distinct projects at Johns Hopkins Medical Center with Dr. Eric Raabe, Dr. Charles Eberhart, and Dr. Fausto Rodriguez

The David Andrysiak Tissue Harvesting Clinical Research Assistant at the Dana Farber Cancer Institute

This CRA position will work within the clinical research program and support the research team in the overall conduct of clinical trials using Good Clinical Practice under the auspices of the Principal Investigator. The CRA will be responsible for the primary data collection and management of patient clinical information as it pertains to participation in clinical trials. They will ensure timely collection of protocol-related samples including shipment to outside entities as required.

• Award $132,000 over 2 years (2019-2021)
• Principal Investigators Dr. Keith Ligon, Associate Professor Pathology, Harvard Medical School, Associate Pathologist/Neuro-Pathologist, Brigham and Women’s Hospital, Dana-Farber Cancer Institute

The Biologic and Prognostic Role of Replicative and Oncogene Induced Senescence

• Principal Investigator Dr. Uri Tabori, Hospital for Sick Children

Targeting the Hedgehog Pathway in Pediatric Low-Grade Glioma

In this proposal, principal investigator Michael K. Cooper, MD, and colleagues at Vanderbilt University Medical Center seek to better define the pediatric glioma subtypes in which the Hedgehog signaling pathway is activated and to determine whether the delivery of Hedgehog signaling inhibitors will halt the growth of these human gliomas in an animal model. This is based on researchers’ previous work which identified compounds that inhibit Hedgehog signaling and determined that the Hedgehog pathway is activated in stem cells in some types of adult gliomas. If successful, these preclinical findings will constitute an important component for developing a novel therapeutic strategy for malignant gliomas and a basis for patient selection.

• Principal Investigator Michael K. Cooper, MD, Vanderbilt University Medical Center

RNAi Screening Core

In the fullness of time, small molecule inhibitors of BRAF may be used for the treatment of BRAF mutant pediatric LGAs. However, multiple protein kinases have been shown to be co-activated in high-grade adult gliomas, and this is likely to be the case in BRAF-transformed pediatric astrocytomas as well. Complimentary signaling pathways are both an obstacle and an opportunity for targeted therapy strategies. An RNAi screening core allows Dr. Chuck Stiles and others at Dana Farber Cancer Institute to conduct a kinome-wide genetic screen for additional druggable protein kinases that cooperate with BRAF to dysregulate the proliferation of normal neural progenitor cells. In addition, RNAi screening complements DNA sequencing as a route to knowledge about other kinds of genes (e.g., GTP-binding proteins, transcription factors) that might underlie these tumors.

• Project Lead Dr. Chuck Stiles, Dana Farber Cancer Institute

PLGA: Dedicated Tumor Banking and Establishment of Cell Lines and Xenografts

A major roadblock hindering investigations into the various types of PLGA is the lack of frozen tissue or renewable tumor models such as cell lines and xenografts. Several factors have contributed to this. First, such tumors are rare, and have not been a research priority at most institutions. Second, surgical resections are often small, and the limited tissue available has gone to pathology for diagnosis, with little or none reserved for research. Finally, because of their relatively indolent growth, it has been difficult to develop cell line or xenograft models.

• Project Leads project by Charles G. Eberhart M.D., Ph.D., Kenneth Cohen M.D., Eli Bar Ph.D., and Peter Burger M.D.