Despite substantial progress in the past two decades, cancer remains the leading cause of death by disease in US children between 1 and 15 years of age. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and cure rates are approaching ~ 80% today. Unfortunately, 20% of children with ALL are not cured with current therapy, making the number of cases of relapsed ALL greater than the total number of new cases of most childhood cancers. Previous work has established that de novo drug resistance is a primary cause of treatment failure in childhood ALL. However, the genomic determinants of drug resistance remain poorly defined. The research supported by this MERIT award has focused on elucidating the genomic determinants of inter-patient differences in drug response in children with ALL, leading to a number of new insights into the pharmacogenomics of childhood ALL. Our scientific aims are focused on some of the most widely used antileukemic agents, thiopurines and glucocorticoids (with complementary studies of L- asparaginase and vincristine).
The first aim i s to identify genes that influence the response to thiopurines (mercaptopurine, thioguanine), using genomewide approaches for gene expression analyses of ALL cells, and SNP analyses of germline and ALL cell DNA to identify SNPs and copy number variations (CNVs) that are significantly related to drug sensitivity and response. Studies in Aim 2 are designed to elucidate these pharmacogenomic traits in T-ALL, a less common subtype that is more resistant to curative chemotherapy, and compare these findings to B-lineage ALL. Once we identify these genes or genome abnormalities (SNPs, CNVs) influencing ALL drug resistance and treatment response, we perform biochemical and genomic studies to determine the mechanism by which these genes or their variants influence the sensitivity of ALL cells to these chemotherapeutic agents. In the continuation of this research program, we are extending our findings from the last 4 years of funding by exploiting new genomewide strategies to identify genomic determinants of drug response (e.g., 1 million SNP arrays, gene expression arrays, mIRNA arrays), to determine whether CNVs or specific mlRNAs modify the expression of genes and thereby alter the sensitivity of ALL cells to these chemotherapeutic agents. Our preliminary findings have indeed revealed specific mlRNAs that influence the sensitivity of ALL cells to these agents, and we have also recently discovered that specific CNVs in ALL cells can significantly influence drug resistance. The continuation of these studies will provide important new insights into the genomic determinants of treatment failure and point to novel targets for developing strategies to overcome drug resistance in childhood ALL.

Public Health Relevance

Pharmacogenomics has great potential to improve public health by minimizing drug-induced side events and improving treatment effectiveness. Acute lymphoblastic leukemia (ALL) the most common cancer in children, serves as a paradigm for a chemotherapy-sensitive malignancy. By capitalizing on the genomic studies which we have already conducted in children with ALL, and exploiting new genomewide technologies, we will define genomic polymorphisms that can be used to design less toxic and more efficacious cancer treatment regimens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA036401-30
Application #
8466934
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wu, Roy S
Project Start
1984-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
30
Fiscal Year
2013
Total Cost
$615,910
Indirect Cost
$236,362
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 :
Li, Jian-Feng; Dai, Yu-Ting; Lilljebjörn, Henrik et al. (2018) Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc Natl Acad Sci U S A 115:E11711-E11720
Heikamp, Emily B; Pui, Ching-Hon (2018) Next-Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia. J Pediatr 203:14-24.e2
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
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
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
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
Landier, Wendy; Hageman, Lindsey; Chen, Yanjun et al. (2017) Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1. J Clin Oncol 35:1730-1736

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