Cracking the Histone Code: A Novel Epigenetic Approach to Pediatric Glioma Diagnosis and Treatment

Project: Research project

Project Details

Description

Pediatric brain tumors are the most common solid tumors of childhood, and are also the most deadly. While a combination of surgery, chemotherapy and radiation can be curative for some pediatric brain tumor patients, the majority of histologic subtypes progress despite multi-modality treatment. In the case of midline and brainstem gliomas, the diffusely infiltrative and anatomic nature of these aggressive tumors preclude surgical resection for disease treatment and medical management has had no effect on overall survival. Nearly all children with high-grade glial tumors, including glioblastoma and diffuse midline gliomas, succumb to their disease within two years of diagnosis1. As a result, despite the best efforts of the neuro-oncologic community, pediatric brain tumors persist as the leading cause of cancer death in children.
However, recent advances in molecular biology and genomic sequencing technology have revealed altered regulation of gene expression, a process known as “epigenetics,” is a key contributor to all types of human disease, including pediatric brain tumors. Novel mutations in genes encoding the histone proteins that regulate gene expression, as well as in enzymes that modify histone protein structure and function, are detected in a majority of high-grade and diffuse midline gliomas1-4. These mutations are associated with altered post- translational modifications to the structure of histone proteins, resulting in the epigenetic signatures (or “histone codes”) that regulate gene expression4-13. These new findings suggest that changes in epigenetic regulation of gene expression may drive pediatric gliomagenesis. Therefore, identifying the epigenetic signatures of pediatric gliomas could: 1) shed new light on the patterns of gene expression that lead to tumor formation; 2) reveal novel therapeutic targets for more effective patient treatment; and 3) yield clinical biomarkers for diagnosis and measuring response to therapy, collectively decreasing disease and treatment morbidity.
In order to address the significant need for improved diagnosis and treatment of this highly morbid pediatric cancer, we describe a novel, hypothesis-driven approach to characterize the epigenetic signatures in clinically accessible pediatric glioma specimens, which may be directly translated to clinical practice in order to ultimately improve patient outcomes.
StatusActive
Effective start/end date1/1/1812/31/20

Funding

  • Northwestern Memorial Hospital (Agmt 1/25/18 - Exhibit B.6)

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