Our lab studies the biology of pediatric brain tumors in order to identify and test novel molecular targets for more effective therapies. Our overarching research goal is to identify biomarkers of disease and develop new therapeutic strategies to improve clinical outcomes for children with brain tumors.
Brain tumors are the most common solid cancer in children. One of the most deadly pediatric brain tumors is high-grade glioma. Typical management of pediatric high-grade gliomas involves surgical removal followed by chemotherapy and radiation. Unfortunately, the five- year survival rate for children with high-grade glioma is only 20%, with the majority of children succumbing to their disease.
Approximately 15% of pediatric brain tumors arise in the brainstem, of which 80% are a subtype known as diffuse intrinsic pontine glioma (DIPG). DIPG is an infiltrative pediatric high-grade glioma affecting young children, with typical onset between 6 and 9 years of age, and has the highest mortality rate of all pediatric solid tumors.Radiation therapy is the standard treatment for DIPG, which temporarily decreases symptoms but has no effect on survival. Despite almost 40 years of clinical trials exploring chemotherapeutic and radiation regimens for children with DIPG, there has been little change in treatment paradigm or overall survival rates: DIPG continues to exhibit the highest mortality rate of all pediatric brain tumors, with median survival less than 12 months and 5-year survival less than 5%.
However, recent studies of pediatric high-grade and brainstem gliomas have provided new insight on the mechanisms of tumor formation and treatment resistance. Analysis of rare tumor specimens have demonstrated that pediatric glioma is a heterogeneous disease characterized by the presence of molecular subgroups. Importantly, missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding Histone H3.3 (H3F3A) and H3.1 (HIST3H1B) have recently been identified in pediatric gliomas, and the H3 K27M driver mutation is correlated with a clinically and biologically distinct subgroup of DIPG patients.
Given the rapid clinical progression of this disease and its poor response to treatment, improved understanding of tumor biology to facilitate development of more effective therapeutic approaches for high-grade pediatric glioma, particularly DIPG, is desperately needed. Our goal is to improve diagnosis and clinical outcomes of pediatric high-grade gliomas through increased understanding of the molecular characteristics of these tumors in order to develop rational, molecularly-informed, targeted therapies for rapid clinical translation.
Amanda Muhs Saratsis, MD