Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and despite remarkable progress in the treatment of ALL (cure has improved from <10 percent to >75 percent), cancer remains the leading cause of death by disease in US children between 1 and 15 years of age. Methotrexate (MTX) is one of the most widely used antileukemic agents and is a component of essentially every ALL treatment protocol worldwide. Our previous work has established the advantage of high-dose (HD) MTX over low-dose, the need for higher doses in T-lineage ALL, and mechanisms for lineage and ploidy differences. However, there is currently >100-fold range in the dosage and infusion time of MTX used to treat childhood ALL, with no consideration of the genetic determinants of treatment response. Furthermore, medical economics have prompted the use of short intravenous infusions of HDMTX (e.g., 4H), so that the treatment can be delivered in an outpatient setting, yet pre clinical studies indicate greater effects with prolonged exposure. Our current research is therefore designed to determine whether 24H is superior to 4H infusion of HDMTX, for each lineage and ploidy subtype of ALL (Aim 1), and to elucidate the genetic determinants of HDMTX intracellular disposition and effects (Aims 2-4).
Aim 1 is addressed in a randomized study of 4H vs. 24H infusions of HDMTX (1 gm/m2) as initial therapy of children with newly diagnosed ALL, comparing cellular accumulation and effects of the active MTX polyglutamate metabolites in bone marrow (BM) leukemia cells and in serial ALL blasts from peripheral blood. Genome-wide assessment of gene expression in ALL cells before and after treatment is used to identify genomic determinants of HDMTX cellular disposition (Aim 2), and identify treatment induced changes in gene expression that discriminate patients who have a good response (i.e., complete inhibition of de novo purine synthesis, >60 percent decrease in ALL cells by day 3, absence of submicroscopic disease in day 19 BM, complete remission at day 42, and long-term disease free survival), from patients who have a poor response (Aim 3).
Aim 4 will identify genetic polymorphisms linked to differences in genomic response of candidate genes that discriminate drug effects. Preliminary data indicate that changes in gene expression can discriminate patients with a good vs. poor response, providing new insights into mechanisms of cellular resistance and revealing potential new targets to augment current treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA078224-06
Application #
6680569
Study Section
Special Emphasis Panel (ZRG1-SSS-O (02))
Program Officer
Wu, Roy S
Project Start
1998-06-01
Project End
2008-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
6
Fiscal Year
2003
Total Cost
$475,929
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Pauley, Jennifer L; Panetta, John C; Crews, Kristine R et al. (2013) Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. Cancer Chemother Pharmacol 72:369-78
Stocco, Gabriele; Yang, Wenjian; Crews, Kristine R et al. (2012) PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. Hum Mol Genet 21:4793-804
Xu, Heng; Cheng, Cheng; Devidas, Meenakshi et al. (2012) ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 30:751-7
Mikkelsen, Torben S; Sparreboom, Alex; Cheng, Cheng et al. (2011) Shortening infusion time for high-dose methotrexate alters antileukemic effects: a randomized prospective clinical trial. J Clin Oncol 29:1771-8
Chen, S-H; Yang, W; Fan, Y et al. (2011) A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Leukemia 25:66-74
Yang, Jun J; Cheng, Cheng; Devidas, Meenakshi et al. (2011) Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet 43:237-41
Pui, Ching-Hon; Pei, Deqing; Campana, Dario et al. (2011) Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 29:386-91
Pui, C H; Pei, D; Sandlund, J T et al. (2010) Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24:371-82
Morris, Van K; Spraker, Holly L; Howard, Scott C et al. (2010) Severe thrombocytopenia with iron deficiency anemia. Pediatr Hematol Oncol 27:413-9
Panetta, John C; Sparreboom, Alex; Pui, Ching-Hon et al. (2010) Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells. PLoS Comput Biol 6:e1001019

Showing the most recent 10 out of 106 publications