High grade pediatric brain tumors (pHGG) are a devastating disease with a median survival of only 9-15 months. Importantly, pHGG represent the greatest cause of cancer related death in children under 19 years of age even though the overall incidence is low (1.78/100,000). In recent years it has become evident that pHGG dramatically differs genetically and molecularly from adult HGG and often different driver mutations have been identified. Chemotherapeutics and targeted agents used in adult GBM studies do not show any survival benefit. We are focusing on a subset of pediatric High Grade Gliomas that are driven by an activated RAS pathway, due to mutations in NF1 (26%), mutations in SETD2 (11%) and/or mutations in ATRX (32%).
Intriguingly, these mutations frequently co-occur (NF1-SETD2 odds ratio of 30.4; NF1-ATRX odds ratio 3.9). It is our goal to validate if SETD2 and ATRX function as tumor suppressors in pHGG and investigate how they mechanistically cooperate with loss of NF1. Additionally, effective therapies for pHGG are lacking.
What are the goals of this project?
The goals of this project are to deconstruct how SETD2 and ATRX loss drives pHGG formation through epigenetic modulation, investigate therapeutic sensitivities of pHGG and determine if loss of NF1, ATRX or SETD2 alters the tumor immune microenvironment through an in depth analysis of pHGG (TMA).
What is the impact of this project?
If we want to develop rational therapies for patients with pHGG, we have to study and understand the intricacies of how mutations in specific genes cooperate and to discover which pathways are key for progression or therapeutic intervention. In this project, we will specifically use cell line based studies and staining for immune infiltration to elucidate how mutations in epigenetic modulators contribute to pHGG formation and evaluate how these mutations confer a therapeutic sensitivity.
Why the CBTN request is important to this project?
The CBTN has a large number of pHGG cell lines and specimens. Additionally both pHGG tumor samples and cell lines have been analyzed in depth providing invaluable data for our projects. Currently, we do not have any human pHGG cell lines in hand and the analysis of human material (cell lines or tissue microarray) nor any tumor samples for staining.
The Children's Brain Tumor Network contributed to this project by providing cell lines and tissue for cell line generation.
Sandro Santagata, Harvard Medical School
Thomas De Raedt, PhD
Dr. De Raedt researches pediatric high grade glioma development and aims to understand the involvement of crucial pathways. He investigates pathway interaction, and explores ways to develop therapies through analyzing human tumors, performing cellular studies, and developing accurate mouse models
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective