Despite increasing cure rates, approximately one fourth of children with acute lymphoblastic leukemia (ALL) eventually die of their disease. The long-term objective of the proposed research is to improve the clinical outcomes of these patients. Early detection of residual disease after remission induction may identify patients who will benefit from intensified treatment, which should then boost the proportion of long-term survivors. During the previous funding period, sensitive immunologic methods of detecting minimal (i.e., submicroscopic) residual disease (MRD) in childhood ALL were developed, and a clinical study demonstrated that MRD detected by these methods is a powerful, independent prognostic indicator. ? ? The main remaining obstacle to the routine incorporation of MRD assays in treatment protocols for childhood ALL is the lack of practical methods that can be successfully applied to all patients. The objective of the studies proposed in Specific Aim 1 is to identify simple antibody panels that allow practical, reliable, and universal flow cytometric monitoring of MRD in children with ALL. Initial findings of cDNA array analyses will be integrated with information derived from comparing the gene profile of normal CD19+CD10+ cells to that of 284 newly diagnosed cases of B-lineage ALL. Flow cytometric studies will focus on proteins selected because of their overexpression in B-lineage ALL cells and their predicted localization on the cell surface. Studies proposed in Specific Aim 2 seek to determine whether detectable MRD in peripheral blood is associated with a more aggressive form of B-lineage ALL as suggested by preliminary results. Studies under this aim will also assess whether the propensity of B-lineage ALL cells to prematurely exit the bone marrow microenvironment is associated with characteristic patterns of expression of adhesion molecules, chemokine receptors or matrix-degrading metalloproteinases. Studies in Specific Aim 3 will determine whether peripheral-blood MRD levels reflect those in the bone marrow in children with T-lineage ALL in clinical remission, as suggested by preliminary results. Success in this endeavor could radically improve remission studies in these patients by overcoming the practical and ethical constraints posed by sequential bone marrow aspirations

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060419-13
Application #
7096533
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wu, Roy S
Project Start
1993-09-01
Project End
2008-07-31
Budget Start
2006-08-04
Budget End
2008-07-31
Support Year
13
Fiscal Year
2006
Total Cost
$256,332
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Coustan-Smith, Elaine; Song, Guangchun; Shurtleff, Sheila et al. (2018) Universal monitoring of minimal residual disease in acute myeloid leukemia. JCI Insight 3:
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
O'Hear, Carol; Inaba, Hiroto; Pounds, Stanley et al. (2013) Gemtuzumab ozogamicin can reduce minimal residual disease in patients with childhood acute myeloid leukemia. Cancer 119:4036-43
Faham, Malek; Zheng, Jianbiao; Moorhead, Martin et al. (2012) Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 120:5173-80
Bhojwani, D; Pei, D; Sandlund, J T et al. (2012) ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia 26:265-70
Coustan-Smith, Elaine; Song, Guangchun; Clark, Christopher et al. (2011) New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood 117:6267-76
Pounds, Stan; Cao, Xueyuan; Cheng, Cheng et al. (2011) Integrated analysis of pharmacologic, clinical and SNP microarray data using Projection Onto the Most Interesting Statistical Evidence with Adaptive Permutation Testing. Int J Data Min Bioinform 5:143-57
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
Metzger, Monika L; Hudson, Melissa M; Krasin, Matthew J et al. (2010) Initial response to salvage therapy determines prognosis in relapsed pediatric Hodgkin lymphoma patients. Cancer 116:4376-84
Stow, Patricia; Key, Laura; Chen, Xiaohua et al. (2010) Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 115:4657-63

Showing the most recent 10 out of 72 publications