Because cancers in children are highly distinct from those in adults, the causes, mechanisms, and therapeutic approaches cannot be extrapolated from the study of adult malignancies. To impact the burden of pediatric cancers requires the specific study of pediatric cancers. This project will characterize three specific subtypes of pediatric malignancies, which together account for over 50% of all pediatric cancer deaths: high grade glioma (pHGG), high risk neuroblastoma (NB), and very high risk acute lymphoblastic B-cell precursor leukemia (VHR-ALL). All three tumor types share the characteristic of typically exhibiting an initial response to therapy followed by the emergence of resistance and refractory disease. We will map molecular and cellular changes in tumor cells, the microenvironment, and the immune system using comprehensive multi-dimensional single-cell and in situ technologies associated with two critical and high-priority transitions: initial response and emergence of resistant disease. Treatment modalities will include standard chemotherapy, molecularly-targeted therapies, and chimeric antigen receptor-T (CAR-T) cell therapy, capturing the cutting edge of current cancer therapy. The final products of this project will include publically available atlases of comprehensive multi-omic, single-cell analysis, critical computational tools and pipelines, and banked biospecimens available to the research community for follow-up studies.
Dr. Kai Tan is a systems biologist and Associate Professor in the Department of Pediatrics, The Children’s Hospital of Philadelphia and University of Pennsylvania. He has extensive experience studying transcriptional and epigenetic regulation in normal development and oncogenesis through a combination of experimental genomics and computational models. Dr. Tan’s laboratory has developed a number of approaches for modeling transcriptional regulatory networks, which have been used to dissect the gene regulatory networks controlling embryonic hematopoiesis, T cell differentiation, and leukemogenesis. In addition, his group has pioneered a number of popular computational algorithms for constructing models of transcriptional regulatory networks by integrating multi-dimensional genomic, epigenomic, and transcriptomic datasets. The ultimate goal of his work is to understand dynamic molecular networks, the role of combinatorial epigenetic modifications and transcriptional regulation, and the role of 3-D genomic organization in gene regulation to improve the diagnosis and treatment of cancer patients.
Dr. Stephen P. Hunger is a pediatric oncologist and Chief of the Division of Oncology, Director of the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia and University of Pennsylvania. His research is focused on improving understanding of the molecular genetics of childhood acute lymphoblastic leukemia (ALL) and translating new discoveries into improved outcomes via clinical trials and linked translational studies. As Vice Chair (2002-2007) and Chair of the Children’s Oncology Group (COG) ALL Committee (2008-2015), he was responsible for overseeing the design and conduct of clinical trials and translational research studies that enroll over 70% of children in the United States with ALL. Dr. Hunger was Principal Investigator of the COG High Risk ALL TARGET Project, which has revealed new sentinel genetic lesions in childhood ALL, identified the Ph-like ALL high risk ALL subtype, and defined its genomic landscape, all of which are discoveries that have led to additional trials testing molecularly targeted therapies.