Oncogenic fusions involving receptor tyrosine kinases (RTK) drive a group of low- and high-grade gliomas (LGG and HGG) in young children. The most common RTK rearrangements involve the oncogenes ALK/ROS1/NTRK/MET and provide an excellent opportunity for therapeutic targeting. These alterations are similar to those observed in multiple unrelated adult and pediatric tumor types, but their roles in gliomagenesis are still largely unknown.
The clinical features and natural history of pediatric RTK-driven gliomas remains uncharacterized. They are more common in infants but also prevalent in older children and adolescents. Interestingly, similar oncofusions drive both benign and malignant gliomas and additional genetic/epigenetic factors are likely to play a role in tumor behavior and explain the clinical heterogeneity.
What are the goals of this project?
In this project, we seek to characterize the genetic, epigenetic and transcriptional landscape of RTK-driven pediatric LGG and HGG. To define clinically-relevant tumor subgroups and assess their prognostic significance, we will evaluate the correlation between molecular and clinical characteristics.
In a first step, we will analyze WGS, WES and RNAseq raw and processed data of gliomas (all grades) already generated by the Children's Brain Tumor Network. Integration of clinical data – including age, histology, tumor location, dissemination, time to progression(s) and overall survival - will allow us to identify the molecular characteristics that dictate clinical presentation and determine benign vs malignant behavior.
In a second step, we intend to expand the cohort and profile additional samples available through CBTN (a detailed separate request will be made for specimen access). Lastly, based on the mechanistic insights gained, we will design and validate new drug combination strategies to accelerate clinical translation.
What is the impact of this project?
Taken together, these studies will provide mechanistic insights into RTK-fused gliomas and enable precision medicine approaches to treat these tumors.
Ana Guerreiro Stücklin, MD, PhD
Dr. Ana Guerreiro Stücklin is a pediatric oncologist. After her medical studies at the University of Porto, Portugal, she graduated from the MD-PhD Program at the University of Zurich and completed her pediatric residency at the University Children’s Hospital in Zurich. She was a pediatric hematolog
University Children's Hospital Zürich
Cynthia Hawkins, MD, PhD, FRCPC
Molecular pathogenesis and therapeutics for paediatric astrocytomas, in particular diffuse intrinsic pontine glioma (DIPG)Identification and clinical implementation of novel prognostic and therapeutic markers for paediatric brain tumours
Uri Tabori, MD
The Tabori lab is focused on combining biological and translational research in paediatric oncology. Specifically, we are interested in studying mechanisms underlying brain tumor immortality and recurrence in the context of predisposition to cancer. Currently our group is studying 3 major areas rela
Adam Resnick, PhD
Adam Resnick is the Director of Data Driven Discovery in Biomedicine (D3b) at Children’s Hospital of Philadelphia (CHOP) responsible for leading a multidisciplinary team to build and support a scalable, patient-focused healthcare and educational discovery ecosystem on behalf of all children. He is a
Children’s Hospital of Philadelphia
Anne-Marie Lyne, PhD
Andreas Postlmayr, PhD
University Children's Hospital Zürich
The University Children’s Hospital Zurich the largest pediatric hospital in Switzerland and one of the leading pediatric centers in Europe. The Department of Oncology at the University Children’s Hospital is part of the Comprehensive Cancer Center Zürich and is in very close proximity to the world r
Children’s Hospital of PhiladelphiaJoined on
Operations Center for the Children’s Brain Tumor Tissue Consortium, the Children’s Hospital of Philadelphia (CHOP) is currently ranked 1st nationally for their Pediatric Cancer Program by U.S. News & World Report. CHOP’s Biobank is home to the CBTTC’s pediatric brain and CNS tumor biorepository; the
High-grade Gliomas (HGG) or astrocytomas 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
Low-Grade Gliomas also called astrocytomas are the most common cancer of the central nervous system in children. They represent a heterogeneous group of tumors that can be discovered anywhere within the brain or spinal cord. Although surgical resection may be curative, up to 20% of children still su