? PROJECT 3 Medications to treat acute lymphoblastic leukemia (ALL) are used for many other malignant and nonmalignant diseases, in adults and in children, but their use is associated with a high risk of adverse effects. Identifying the genetic and non-genetic risk factors (e.g. age, treatment arm) for these adverse effects is essential to improve use of these medications to minimize the morbidity and mortality of these agents for non-ALL patients as well as for improving outcomes in ALL. We have strong preliminary data that the risks of adverse effects of ALL chemotherapy are at least partly heritable, but there has been a lack of cohort-based, systematic genome-wide approaches to rigorously define these risk factors. In Project 3, our goal is to identify the genetic and non- genetic risk factors for the most important adverse effects of commonly used ALL medications in children and adults. An important characteristic of our Center is that we are studying cohorts of patients (~ 6600 children and ~ 600 adults) enrolled on front-line clinical ALL trials, rather than using a health-records based or case- control approach. Advantages to this approach include: elimination of bias in case/control selection; administration of therapy is uniform, controlled, and documented; standardized assessment across trials that uses a common system for grading type and severity of adverse effects; ascertainment of non-genetic risk factors that are used as covariates in all analyses; and cost effectiveness, in that patients with and without the phenotype are analyzed for multiple other adverse events. Also, many of the same patients (and DNA) studied for assessing risk factors for adverse effects (Project 3) are also studied for assessing treatment outcomes (Project 1) and drug sensitivity (Project 2). For the first time, we are using a common approach to both pediatric (COG and SJCRH) and adult (CALGB/Alliance and ECOG) pharmacogenomic studies. Using genome-wide interrogations (Core B), we will determine the host- and treatment-related risk factors for four serious adverse effects: osteonecrosis (primarily due to glucocorticoids), hepatotoxicity (primarily due to asparaginase and methotrexate), vincristine-induced neuropathy, and pancreatitis (primarily due to asparaginase) in the Center?s core clinical trials. We will perform primary discovery in the pediatric trials, test for validation in adult trials, and separately analyze the adult-only and the combined pediatric and adult cohorts. We use state-of-the-art computational tools to annotate and prioritize variants using a common pipeline (as in Projects 1 and 2, Core C) for the four primary phenotypes. The highest priority variants will be assessed in preclinical models, to determine the mechanisms by which the top genetic and non-genetic risk factors affect the risk of osteonecrosis, as an example phenotype. We will combine the risk factors for adverse effects identified in Project 3 with those identified in Projects 1 and 2 for antileukemic response to contribute to an overarching aim for the Center (Aim 1 of Core C): to form the foundation for an approach to more precisely assign patients to regimens that minimize adverse effects while maintaining desired antileukemic effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM115279-04
Application #
9509479
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
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
Zhang, Yingchi; Gao, Yufeng; Zhang, Hui et al. (2018) PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia. Blood 131:2256-2261
Gupta, Sumit; Devidas, Meenakshi; Loh, Mignon L et al. (2018) Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group (COG). Leukemia 32:1370-1379
Steeghs, Elisabeth M P; Bakker, Marjolein; Hoogkamer, Alex Q et al. (2018) High STAP1 expression in DUX4-rearranged cases is not suitable as therapeutic target in pediatric B-cell precursor acute lymphoblastic leukemia. Sci Rep 8:693
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
Churchman, Michelle L; Qian, Maoxiang; Te Kronnie, Geertruy et al. (2018) Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell 33:937-948.e8
Browne, Emily K; Zhou, Yinmei; Chemaitilly, Wassim et al. (2018) Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia. Cancer 124:4248-4259
Diouf, Barthelemy; Evans, William E (2018) Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy: Progress Continues. Clin Pharmacol Ther :
Robinson, Katherine M; Yang, Wenjian; Haidar, Cyrine E et al. (2018) Concordance between glucose-6-phosphate dehydrogenase (G6PD) genotype and phenotype and rasburicase use in patients with hematologic malignancies. Pharmacogenomics J :
Green, Daniel M; Wang, Mingjuan; Krasin, Matthew J et al. (2018) Serum ALT elevations in survivors of childhood cancer. A report from the St. Jude Lifetime Cohort Study. Hepatology :

Showing the most recent 10 out of 72 publications