Pediatric brain tumors are the leading cause of disease related death in children. Major factors contributing to treatment failures for children with brain tumors include: i) the lack of comprehensive molecular description of the disease and an associated dearth of integration of the tumors’ biological signatures at gene, protein and RNA levels; ii) paucity of comprehensive and molecularly-driven preclinical tests for informing precision-targeting disease pathways; and iii) lack of sensitive methods of assessing tumor response to treatment. Furthermore, while surgery remains the mainstay of pediatric brain tumor treatment, many tumors are non-resectable and/or progressive/disseminated tumors lead to significant tumor-related morbidity. In contrast to adults, tumors in central nervous system are often challenging to treat with traditional chemotherapy and radiation resulting in long-term neuro-toxicities in the context of the developing brain.
While pediatric cancers have benefited from large-scale genomics efforts lead by the NIH in the context of TARGET (Therapeutically Applicable Research To Generate Effective Treatments), brain tumors are not represented in these cohorts. The consortia-based efforts of the Children's Brain Tumor Network and the Pacific Pediatric Neuro-Oncology Consortium and associated platforms were complemented with the launch of CAVATICA (cavatica.org), a scalable, cloud-based storage and compute environment providing comprehensive, secure, and integrated access to pediatric cancer genomic data that is further integrated with additional rare-disease-genomic data. These early efforts are now undergoing significant expansion through the Commons Fund’s Kids First Program and CHOP’s role in leading the development of the Kids First Data Resource Center (DRC) along with its partners at the Ontario Institute for Cancer Research, the University of Chicago, Children’s National Health System, the Oregon Health and Science University and Seven Bridges. The Kids First DRC will support accelerated scientific discovery across more than >20,000 WGS from dozens of childhood cancer and structural birth defects cohorts being sequenced over the next 2 years. It is in this context of emerging genomic data and a data commons architecture that we propose to define a discovery cohort for comprehensive proteomic analysis in pediatric brain tumors.
What are the goals of this project?
We propose to perform comprehensive quantitative and associated post translational analyses on a pilot cohort
What is the impact of this project?
Our own and other’s efforts in characterizing pediatric brain tumors have defined their biologic underpinnings as distinct from adult brain tumors. Compared to adults, pediatric cancers possess significantly fewer driver mutations. Furthermore, in addition to canonical respective loss/gain of tumor suppressors/oncogenes, gene fusions events provide a common driving genetic mechanism. However, such structural variations also impinge on the epigenetic landscape in ways only recently appreciated. Indeed, especially in high-grade tumors, epigenetic dysregulation provides a common and ubiquitous paradigm for pediatric brain tumors likely informed by the developmental context of the central nervous system. Our own recent proteomic analyses of DIPGs, where histone mutations (“onco-histones”) have been identified, have focused on histone posttranslational modification and the potential therapeutic role of HDACs in modulating such epigenetic dysregulation. To date, few proteomic studies have been defined for pediatric cancer.
Why the CBTN request is important to this project?
The CBTTC collects longitudinal, deep clinical, and phenotypic data on all prospective patients. More than 900 distinct flash-frozen specimens have been collected since 2011 across all brain tumor histologies with >75 mg of tissue and paired blood (germline) and are undergoing WGS/RNAseq (~200 samples have been completed).
The Children's Brain Tumor Network contributed to this project by contributing over 200 samples and by providing access to the Pediatric Brain Tumor Atlas.
● Fred Hutch: Amanda Paulovich
● Harvard: Steven Gygi
● NIH: Kinsinger, Christopher (NIH/NCI)
● NIH: Rodriguez, Henry (NIH/NCI)
● NIH/NCI: Boja, Emily (NIH/NCI)
● NIH/NCI: Bocik, William (NIH/NCI)
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 i
Children’s Hospital of Philadelphia
Brian Rood, MD
Brian R. Rood, MD, is an Associate Professor of Pediatrics in the Center for Cancer and Blood Disorders at Children’s National Hospital whose primary clinical focus is pediatric neuro-oncology. Dr. Rood joined the faculty of Children’s National in 2002 after completing a fellowship in Pediatric H
Children’s National Hospital
Javad Nazarian, PhD, MSc
I am an investigator at the Center for Genetic Medicine in Children’s National Hospital in Washington, D.C., and an assistant professor in Integrative Systems Biology at the George Washington University. I received my PhD from the George Washington University in Genetics in 2005. My dissertation
Children’s National Hospital
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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
Atypical teratoid/rhabdoid tumor (AT/RT)
Atypical teratoid/rhabdoid tumor (AT/RT)
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Schwannoma is a rare type of tumor that forms in the nervous system. Schwannoma grows from cells called Schwann cells. Schwann cells protect and support the nerve cells of the nervous system. Schwannoma tumors are often benign, which means they are not cancer. But, in rare cases, they can become
Proteomic Analysis of CBTN Cell Lines (Procan)
Scientists at Children’s Medical Research Institute are analysing tens of thousands of examples of all types of cancer from all over the world to develop a library of information to advance scientific discovery and enhance clinical treatment worldwide.This database will mean doctors can ef
HGG, Atypical teratoid/rhabdoid tumor (AT/RT)
Pediatric brain tumor miRNA profiling for the cohort of Children’s Brain Tumor Tissue Consortium specimens
Pediatric brain tumors are the leading cause of disease related death in children. Major factors contributing to treatment failures for children with brain tumors include: a) the lack of comprehensive molecular characterization involving integration of the DNA-RNA-protein profiling; b) comprehens
Craniopharyngioma, Medulloblastoma, HGG, Atypical teratoid/rhabdoid tumor (AT/RT), LGG, Ependymoma, Ganglioglioma, DNET, Schwannoma
Project Hope: High-Grade Glioma-Omics in Pediatric and AYA
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