In this application for the Pharmacogenomics of Anticancer Agents Research in Children (PAAR4Kicls), the goal is to fully define the pharmacogenomics of childhood acute lymphoblastic leukemia (ALL), the most common childhood malignancy, in order to improve the lives of children with this disease, as well as any patients treated with the same medications.
Our aims are to define genomic variations (germline and acquired) important for interpatient variability in treatment response and toxicity from medications used to treat childhood ALL, to translate pharmacogenomics into clinical treatment strategies, and to collaborate with pharmacogenomics investigators to leverage relevant pharmacogenomic knowledge from pediatric ALL to other diseases and disciplines (and wee-versa). This is accomplished by a multidisciplinary team of leaders in the field. The research harnesses the power of studying patients with ALL treated on Children's Oncology Group (COG) and St. Jude Children's Research Hospital protocols, achieving near-population-level coverage for ALL in the US. Pediatric ALL provides outstanding opportunities for pharmacogenomic discoveries and translation to the clinic, because this is an otherwise fatal disease that is cured through extensive use of agents that have a narrow therapeutic index. The agents are broadly used in cancer and in general medical practice and thus the findings from PAAR4Kids have applicability outside of pediatric ALL, as demonstrated by multiple collaborations within and outside of the PGRN. PAAR4Kids studies the pharmacogenomics, pharmacokinetics (cellular and plasma), antileukemic and toxic effects of glucocorticoids, methotrexate, thiopurines, asparaginase, anthracyclines, and vincristine. The approach is summarized in four major Steps. In Step 1 genotype/phenotype studies are undertaken in a set of core phase III front-line clinical trials involving over 10,000 patients that serve as discovery and replication cohorts. Non-genetic covariates are included. In Step 2, genomic variation is prioritized for further follow-up. Step 3 is confirmation and validation, consisting of mechanistic experimental laboratory models, surveys of human tissues, and/or additional genotype/phenotype analyses in other clinical trials, often using PGRN resources. In Step 4, validated genomic associations with large effect sizes are integrated into clinical settings. PAAR4Kids has world class scientists applying state-of-the-art genomics techniques to the germline and tumor cells of impeccably cataloged specimen collections from extensively phenotyped patients, and outstanding statisticians, pharmacologists, and clinicians. PAAR4Kids is poised to comprehensively attack the pharmacogenomics of childhood ALL.

Public Health Relevance

Acute lymphoblastic leukemia is the most common cancer in children. Using multiple medications, many of which are also often used to treat other cancers and non-cancer conditions in adults and children, some patients are cured but not others, and some have severe side effects. By unraveling the genomic basis of variability in medication response, this research will lead to increased safety and effectiveness of these medications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01GM092666-04
Application #
8501544
Study Section
Special Emphasis Panel (ZRG1-GGG-M (52))
Program Officer
Long, Rochelle M
Project Start
2010-07-15
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$1,776,954
Indirect Cost
$565,859
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Diouf, Barthelemy; Lin, Wenwei; Goktug, Asli et al. (2018) Alteration of RNA Splicing by Small-Molecule Inhibitors of the Interaction between NHP2L1 and U4. SLAS Discov 23:164-173
Pui, Ching-Hon (2018) To delay or not to delay, that is the question for patients with acute lymphoblastic leukemia who do not receive prophylactic cranial irradiation. Cancer 124:4442-4446
Diouf, Barthelemy; Evans, William E (2018) Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy: Progress Continues. Clin Pharmacol Ther :
Dvorak, Christopher C; Satwani, Prakash; Stieglitz, Elliot et al. (2018) Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr Blood Cancer 65:e27034
Clay-Gilmour, Alyssa I; Hahn, Theresa; Preus, Leah M et al. (2017) Genetic association with B-cell acute lymphoblastic leukemia in allogeneic transplant patients differs by age and sex. Blood Adv 1:1717-1728
Luzum, J A; Pakyz, R E; Elsey, A R et al. (2017) The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems. Clin Pharmacol Ther 102:502-510
Gausachs, Mireia; Borras, Ester; Chang, Kyle et al. (2017) Mutational Heterogeneity in APC and KRAS Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis. Clin Cancer Res 23:5936-5947
Chhibber, A; French, C E; Yee, S W et al. (2017) Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines. Pharmacogenomics J 17:137-145
Karol, S E; Larsen, E; Cheng, C et al. (2017) Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia. Leukemia 31:1325-1332
Stock, W; Diouf, B; Crews, K R et al. (2017) An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia. Clin Pharmacol Ther 101:391-395

Showing the most recent 10 out of 155 publications