The Saratsis 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.
Characterizing the role of Tenascin-C (TNC) in pediatric glioma as a marker of tumorigenesis and novel therapeutic target
We previously identified increased Tenascin-C (TNC) protein expression in tumor tissue and cerebrospinal fluid (CSF) in DIPG patients, with highest TNC expression levels observed in K27M mutants. TNC is an extracellular matrix protein that modulates the mitogenic effects of PDGF and NOTCH signaling in oligodendroglial precursor cells (OPCs), the purported cells of origin for DIPG. In adult glioma, TNC expression is associated with NOTCH activation, which is a component of the Hh pathway. TNC overexpression in adult glioma correlates with tumor recurrence, local invasion and poor overall survival. However, the role of TNC expression in pediatric gliomas, and its potential as a therapeutic target, has yet to be explored.
Through a series of in vivo and in vitro studies, we aim to characterize the nature, frequency and variation in level of TNC overexpression in pediatric HGG and DIPG cell lines, tumor tissue, serum and CSF. The molecular and effects of modulating TNC expression on tumor cell biology and function are investigated in vitro and in vivo in order to determine the mechanism of TNC overexpression in pediatric glioma and its role as a novel therapeutic target.
Exploring the Histone H3K27M mutation as a driver of pediatric gliomagenesis
Epigenetic regulation of gene expression has been implicated in a variety of human diseases, including cancer. Recently, point mutations in histone H3 have been identified in up to 80% of pediatric midline gliomas, causing altered chromatin function and extensive transcriptome reprogramming. Our group is working to elucidate the mechanism by which histone H3 post-translational modifications in H3K27M mutant glioma alter gene transcription to contribute to tumor formation and progression. Integrating RNA-Seq, ChIP-Seq and proteomic analysis of rare patient-derived tumor specimens and primary glioma cell lines, we are working to identify epigenetic “signatures” of disease and characterize alterations in gene expression in DIPG associated with specific histone H3 transcriptional regulatory marks. In turn, we are evaluating the enzymatic mechanisms responsible for these histone modifications to determine if these represent rational therapeutic targets. Importantly, our group recently demonstrated that H3 mutations are detectable in the cerebrospinal fluid (CSF) from patients with midline and supratentorial hemispheric glioma. We are therefore working to expand this “liquid biopsy” approach for mutation detection for clinical tumor diagnosis, stratification to targeted therapy and monitoring treatment response.
Amanda M. Saratsis, MD Attending Physician, Division of Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago Attending Physician & Director of Congenital Disorders, Department of Neurological Surgery, Northwestern Memorial Hospital Assistant Professor, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine firstname.lastname@example.org email@example.com
Melissa M. Vazquez, BS , Executive Assistant, Department of Neurological Surgery Northwestern University Feinberg School of Medicine Phone: 312.503.4877 Fax: 312.503.3552 firstname.lastname@example.org 300 East Superior Tarry 2-725 Chicago, IL 60611 Phone: 312.503.4345