Building on our success as world leaders in acute lymphoblastic leukemia (ALL) and as leaders in the Pharmacogenomics Research Network (PGRN), we have formed a Center for Precision Medicine in Leukemia. Our goal is to identify the mechanisms underlying interpatient variability in response to antileukemia medications. We will integrate state-of-the-art genomic, transcriptomic, and epigenomic interrogation of somatic cell ALL tumor cells, host germline DNA variation, and comprehensive assessment of treatment variables and non-genetic features in children and adults with ALL, coupled with laboratory mechanistic studies, to identify sources and mechanisms of interpatient variation in response. Many ALL medications are also used to treat other pediatric and adult cancers and also nonmalignant diseases: for example, glucocorticoids, methotrexate, and thiopurines are commonly used for nonmalignant diseases such as asthma, autoimmune, and inflammatory diseases, and so ALL can serve as a model for how to optimize use of therapy that will have broad implications beyond ALL. Our investigators include leaders in adult and childhood ALL, pharmacogenomics, human genomics, clinical pharmacology, computational biology, bioinformatics, and biostatistics. We have three major aims, addressed in three highly integrated projects (all of which capitalize on front-line ALL clinical trials) and three Center cores. In Proect 1, we will define the landscape of genome variation among ALL subtypes and identify the inherited and somatically acquired genomic variation, along with other clinical features, that are associated with ALL treatment response in patients. In Project 2, we will identify the genome variation associated with de novo and acquired drug resistance in primary ALL cells from patients at diagnosis and at relapse, and will elucidate mechanisms by which genomic variation influences drug resistance and treatment response. In Project 3, we will identify genomic variation associated with specific serious adverse effects of antileukemic agents (osteonecrosis, hepatotoxicity, pancreatitis, and neuropathy), establishing mechanisms and testing interventions for the phenotype of osteonecrosis. Synergies in the Center stem from the substantial overlap in patients and genomic data among the three projects; the complementary expertise and prior collaborations among investigators; the leadership of our Administrative Core with extensive ties to existing pharmacogenomic, genomic, and clinical cancer networks; and uniform approaches to data analysis, management, integration, and deposition provided by our Cores. Our Center's overarching aim is to use the knowledge gained from the research in the three projects to build a comprehensive precision medicine approach to minimize relapse while also minimizing adverse effects. This Center will allow us to engage additional adult ALL and genomics collaborators, accelerate progress in the discovery and translation of genomics into more effective and less toxic treatments, and provide a paradigm for other diseases for the integration of genomic methods and knowledge into precision medicine.

Public Health Relevance

Acute lymphoblastic leukemia is the most common tumor in children and is very responsive to medications, but outcomes are much worse in adults. This center identifies the genetic and non-genetic risk factors for tumor relapse and for serious adverse effects of the medications, and will build new models for how to precisely match patients to medication regimens to maximize cure and minimize adverse effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM115279-01
Application #
8933498
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Long, Rochelle M
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Hardy, Kristina K; Embry, Leanne; Kairalla, John A et al. (2017) Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children's Oncology Group. J Clin Oncol 35:2700-2707
Liu, C; Yang, W; Pei, D et al. (2017) Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait. Clin Pharmacol Ther 101:373-381
Park, H-W; Tse, S; Yang, W et al. (2017) A genetic factor associated with low final bone mineral density in children after a long-term glucocorticoids treatment. Pharmacogenomics J 17:180-185
Eissa, H M; Zhou, Y; Panetta, J C et al. (2017) The effect of body mass index at diagnosis on clinical outcome in children with newly diagnosed acute lymphoblastic leukemia. Blood Cancer J 7:e531
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Abraham, Brian J; Hnisz, Denes; Weintraub, Abraham S et al. (2017) Small genomic insertions form enhancers that misregulate oncogenes. Nat Commun 8:14385
Roberts, Kathryn G; Gu, Zhaohui; Payne-Turner, Debbie et al. (2017) High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. J Clin Oncol 35:394-401
Pui, C-H; Pei, D; Raimondi, S C et al. (2017) Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia 31:333-339
Moriyama, Takaya; Yang, Yung-Li; Nishii, Rina et al. (2017) Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood 130:1209-1212

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