Funded Projects

Long Term Clinical Implications of PLGG Molecular Subgroups

Pediatric low grade gliomas possess the dichotomy of excellent (greater than 90%) short term overall survival with very low (less than 40%) progression-free survival leading to the following major clinical challenges: Multiple recurrences resulting in accumulation of toxic therapies, significant but extremely variable long term morbidity resulting in late mortality, and multiple pathological subgroups lumped together resulting in lack of specific and targeted therapies. In this project, in order to address these issues, Dr. Uri Tabori and colleagues at Sick Kids of Toronto hypothesize that uncovering RAS/MAPK alterations in all PLGG subtypes as well as secondary events in these cancers will enable novel molecular risk stratification of PLGG. This novel classification will guide current and future targeted therapies which are becoming available for these tumors.

• Principal Investigators Dr. Uri Tabori, Sick Kids of Toronto

Identification of the Molecular Signature of Progressive JPA

Pilocytic astrocytomas (PA), the most common childhood brain tumor, is classified into 2 groups: those that are resected and do not recur (non-progressors), and those that recur early and need further treatment, progressors. There is little that distinguishes these patients at diagnosis, a fact which leads to uncertainty regarding the need for further treatment on the part of the physician and uneasiness and worry about the long-term outcome for their children on the part of the parent.

• Principal Investigators Elizabeth Maher, MD, PhD

Identification of Key Genetic and Growth Control Pathway Changes in JPA

A collaborative project led by principal investigators Dr. David Gutmann and Dr. Tobey MacDonald at Washington University to conducting the first truly comprehensive genomic, genetic and proteomic analysis of JPAs. This project applies cutting edge bioinformatics techniques to proven genetic, genomic and proteomic analyses which have helped lead to the development of “targeted therapeutics” in a number of adult cancers. A Kid’s Brain Tumor Cure recognizes the Brain Tumor Society (BTS) Boston for their support on this project.

• Principal Investigators Dr. David Gutmann and Dr. Tobey MacDonald at Washington University

Identification of Key Genetic and Growth Control Pathway Changes in Fibrillary Astrocytoma that Represents Potential Molecular

This study, led by principal investigators Dr. David Gutmann and Dr. Tobey MacDonald of Washington University, represents a collaborative project that builds upon a 2006 project funded by Brain Tumor Society (BTS) Boston. The 2006 project resulted in the first truly comprehensive genomic, genetic and proteomic analysis of juvenile pilocytic astrocytomas (JPAs). This new project will focus on pediatric fibrillary astrocytomas (PFA) as it continues to employ multiple complementary high-throughput technologies to identify key molecular genetic changes (DNA, RNA and protein) and growth control pathways that represent potential molecular targets for future therapeutic drug design.

• Principal Investigators Dr. David Gutmann and Dr. Tobey MacDonald of Washington University

Human iPSC PLGA Models for Drug Discovery

Pediatric low-grade astrocytomas (PLGAs) are benign brain tumors that have proven difficult to maintain as cell lines in vitro or as patient-derived xenografts in vivo. These obstacles reflect numerous critical features that distinguish PLGAs from their malignant counterparts.

• Award $300,000 over 3 years (2019-2022)
• Principle Investigators Dr. David Gutmann, The Washington University in St. Louis

Genomic Analysis of Matched Primary and Progressive Recurrent PLGAs

This position works within the Pediatric Neuro-Oncology Program at the Dana-Farber/Children’s Hospital Cancer Center as well as the Center for Neuro-Oncology at Dana-Farber Cancer Center, the Neurosurgery and Neuropathology Departments at Brigham and Women’s Hospital and Children’s Hospital Boston to facilitate tissue banking at these hospitals. Tissue banking is the storage of a patient’s tumor tissue, blood, and other specimens collected at the time of surgery or during other clinical collections for use in future research and clinical trials that the patient may choose to participate in. The main goals of this position are to increase the number of patients consented to tissue banking, facilitate the banking of specimens at the time of surgery, and help ensure that all pathology review required as part of clinical trials is completed.

Genetic Characterization Grade II LGA

This study by Dr. Chuck Stiles at Dana Farber Cancer Institute will perform a proof of concept study to determine the optimal strategy for comprehensively characterizing somatic genetic events in individual tumors with a focus on grade II pediatric astrocytoma. The research team anticipates that these studies will determine the important oncogenes and tumor suppressor genes that drive pediatric low-grade glioma development. They also anticipate that an understanding of the molecular pathways disrupted by these mutations will guide the development of rational therapeutics for this disease. If successful, it will enable rapid follow-up with an extended characterization of larger numbers of tumors to identify the recurrent events that cause this disease.

• Principal Investigator Dr. Chuck Stiles, Dana Farber Cancer Institute

Functional Engagement and Effect of RAF-targeted Therapies in Glioma

An accurate understanding of drug penetration, target inhibition in the brain, and prognostic biomarkers is lacking in PLGA. This is due in part to the limitations of obtaining serial biopsies from patients with brain tumors. Detailed genomic characterization over the past decade has revealed that, while PLGA is a distinct entity, it shares some molecular drivers with pediatric HGG (pHGG) and adult HGG (aHGG).

• Award $180,000 over 2 years (2020-2022)
• Principal Investigators Dr. Karisa Schreck, Assistant Professor of Neurology, Johns Hopkins University-School of Medicine

Evaluation of MYBL1 Fusion Oncogene in Pediatric Diffuse Astrocytoma

Pediatric diffuse astrocytomas are rare but represent a major clinical problem in pediatric neuro-oncology due to their heterogeneous pathology and unpredictable clinical behavior. Unlike adult gliomas researchers’ understanding of the molecular mechanisms which drive tumorigenesis within pediatric low grade gliomas are largely unknown.

• Principal Investigators Dr. Keith Ligon, Dana-Farber Cancer Institute

Establishment of PLGA Research Program at Dana Farber Cancer Institute

In May 2007, PLGA Fund at PBTF funded the establishment of the first dedicated PLGA research program at the Dana Farber Cancer Institute. The initial $2 million grant helped concentrate resources on research into pediatric low-grade brain tumors in order to discover new and improved targeted therapies that don’t risk impairing children’s bodies and minds. This is believed to be the first coordinated research effort committed to this specific type of tumor worldwide.