Uncovering how genetics can be used to tailor cancer therapy in children
Leukemia is the most common pediatric cancer, but it exhibits profound differences from patient to patient. Individuals vary widely with regard to risk of developing the disease, and propensity for developing drug resistance or treatment toxicity. Our laboratory uses a genomic-based approaches to decipher the mechanisms that drive these differences. Our goal is to determine how variations in genetic makeup can be leveraged to predict and improve response to leukemia therapy in children.
Driven by observations of inter-individual variations in patients with pediatric leukemia, our research is dedicated to understanding how genetic variation dictates this diversity. We take an agnostic and genome-wide view, to explore genetic factors across the entire human genome in large cohorts of patient with different phenotypes (e.g., drug resistance or toxicity). From there, we identify specific genes related to these traits, and interrogate them to understand the mechanism linking a particular genetic variant to a particular phenotype. We are particularly proud of our close collaborations with clinical investigators and the global diversity in pediatric leukemia we study.
Using pharmacogenomics to develop novel therapies for pediatric leukemia
Although the cure rate of pediatric leukemia is high, this was achieved by brute-force approach using cytotoxic chemotherapy for decades. We are leading efforts at St. Jude to develop the next generation of leukemia therapy with surgical precision, leveraging genetic insights developed over the past 10 years. Studying 1000+ leukemia patients across the US, we are examining their pharmacotype and profiling genomes at the same time. Our aim is to construct a gene-drug connectivity map to identify biomarkers and predictors of patients’ response to novel leukemia drugs. We have already started developing a biomarker-informed clinical trial for pediatric T-ALL based on this work and look forward to applying this approach to other subtypes of ALL.
Using pharmacogenomics to predict treatment toxicity
The drugs currently used to treat pediatric leukemia are highly efficacious, but with profound adverse effects. It is important that we understand the underlying causes of toxicity and try to mitigate this deleterious response in patients. Again, our team takes a genomic approach – comparing patients with vs without toxicity in genome-wide scans to identify specific variants associated with the side effects. Our group discovered genetic polymorphism in the NUDT15 gene that puts children at a dramatic risk of myelosuppression following treatment of an anti-leukemia drug called thiopurine. By elucidating the molecular mechanism of how NUDT15 modulates thiopurine metabolism, we developed ways to use pharmacogenomics to individualize their therapy, reducing associated toxicities by almost 90%. This work has led to the change of thiopurine drug label by the Food and Drug Administration. We are currently exploring pharmacogenomics of other pediatric cancer drugs.
Determining genetic risk factors for developing leukemia
Fundamental to our work is the understanding that children are at varied risk for developing leukemia. We use genome wide studies to explore the genetic variants that drive the formation of leukemia. Our laboratory, in collaboration with other investigators at, and beyond, St. Jude, has developed cohorts of children with leukemia, and their healthy counterparts. We compare the genetic makeups of each population and identify putative risk factors – genes enriched in afflicted children. Additionally, we work to identify rare families with multiple cases of leukemia, suggesting highly penetrant genetic risk factors. We utilize engineered mouse models to manipulate genes of interest identified in these studies and investigate the resulting hematopoietic phenotypes. Ultimately, our goal is to understand the genetic basis for susceptibility to pediatric leukemia.
Dr. Jun J. Yang has a long-standing interest in human genetics, dating back to his early education in China where he received his undergrad and master’s degrees. He completed his PhD training at Purdue University and moved to St. Jude where he transitioned from postdoc training to faculty in 2010. Dr. Yang currently serves as Vice Chair for the Department of Pharmacy and Pharmaceutical Sciences and is the Associate Director of the Hematological Malignancies T32 Training Program at the St. Jude Comprehensive Cancer Center. He was elected President of the Pharmacogenomics Research Network in 2021. Dr. Yang has been continuously funded by the NIH since 2011 and receives funding from prestigious nonprofit organizations including the V Foundation. Dr. Yang is committed to genomic and pharmacogenomic research of pediatric leukemia and leverages multi-disciplinary collaborations to ask scientific questions on a global scale.
Dedicated and diverse team of scientists with backgrounds ranging from clinical pediatric hematology/oncology training to experimental biology and bioinformatics.