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Grant Details

Grant Number: 5R01CA127642-03 Interpret this number
Primary Investigator: Lipshultz, Steven
Organization: University Of Miami School Of Medicine
Project Title: Genetic Mechanisms of Anthracycline Cardiotoxicity in Pediatric Cancer Survivors
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Long-term survivors of childhood cancer (LTS) have greater than an 8-fold increased risk of CV mortality compared to a healthy population 25 years after therapy. This risk increases progressively over time and appears related in part to anthracycline chemotherapy. Since 1:570 young adults in the US aged 20-45 by 2010 is projected to be a childhood cancer survivor and half will have had anthracycline therapy, the mechanism of this toxicity to prevent or treat it becomes critical to understand. Genetics (either natural genotypes or induced changes) may play a role in the susceptibility of anthracycline toxicity for each individual. In animal models of anthracycline cardiotoxicity, irreversible mitochondrial impairment, in part related to free-radical injury during therapy, leading to late cardiomyopathy is found but this has not been studied in humans. Mutations of the genes know to cause hemochromatosis (HFE mutations) may also lead to susceptibility to toxicity. In this application, Aim 1 will be to determine the frequency of mitochondrial DNA (mtDNA) mutations in pediatric acute lymphoblastic leukemia (ALL) survivors enrolled in the Dana Farber Cancer Institute Consortium. We will also determine if there are differences in mutation rates between children who received the cardioprotectant, dexrazoxane, versus those who did not. We will correlate the degree of mutations to other markers of cardiac function (echocardiographic measures and serum biomarkers of cardiac risk). Aim 2 will determine if HFE mutations are associated with greater long-term cardiotoxicity as measured by echocardiography and serum biomarkers. We will enroll a total of 200 ALL survivors enrolled in the DFCI ALL consortium who were enrolled in studies 91-001, 95-001, and 00-001. Only 50% will have received the cardioprotectant, dexrazoxane. mtDNA and HFE studies will be obtained >4 years from diagnosis with simultaneous evaluation of cardiac function via echocardiography and analysis of serum biomarkers of cardiac risk (lipids, proBNP, hsCRP, cTnT). We will determine: 1. If there is a higher frequency of mtDNA mutations associated with prior anthracycline treatment and if dexrazoxane is protective against these mutations 2. If mtDNA mutation relate to increased CV risk of cardiomyopathy, premature atherosclerosis; 3. If the HFE mutations are related to increased cardiotoxicity of anthracyclines. This study will elucidate the molecular mechanisms of anthracycline cardiotoxicity in pediatric ALL cancer survivors.

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Publications

Treatment-related cardiotoxicity in survivors of childhood cancer.
Authors: Lipshultz SE, Cochran TR, Franco VI, Miller TL
Source: Nat Rev Clin Oncol, 2013 Dec;10(12), p. 697-710.
EPub date: 2013 Oct 29.
PMID: 24165948
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Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia.
Authors: Lipshultz SE, Lipsitz SR, Kutok JL, Miller TL, Colan SD, Neuberg DS, Stevenson KE, Fleming MD, Sallan SE, Franco VI, Henkel JM, Asselin BL, Athale UH, Clavell LA, Michon B, Laverdiere C, Larsen E, Kelly KM, Silverman LB
Source: Cancer, 2013 Oct 1;119(19), p. 3555-62.
EPub date: 2013 Jul 16.
PMID: 23861158
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Dietary quality, caloric intake, and adiposity of childhood cancer survivors and their siblings: an analysis from the cardiac risk factors in childhood cancer survivors study.
Authors: Landy DC, Lipsitz SR, Kurtz JM, Hinkle AS, Constine LS, Adams MJ, Lipshultz SE, Miller TL
Source: Nutr Cancer, 2013;65(4), p. 547-55.
PMID: 23659446
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Ingesting and aspirating dry cinnamon by children and adolescents: the "cinnamon challenge".
Authors: Grant-Alfieri A, Schaechter J, Lipshultz SE
Source: Pediatrics, 2013 May;131(5), p. 833-5.
EPub date: 2013 Apr 22.
PMID: 23610205
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Exercise capacity in long-term survivors of pediatric cancer: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study.
Authors: Miller AM, Lopez-Mitnik G, Somarriba G, Lipsitz SR, Hinkle AS, Constine LS, Lipshultz SE, Miller TL
Source: Pediatr Blood Cancer, 2013 Apr;60(4), p. 663-8.
EPub date: 2012 Dec 19.
PMID: 23255294
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Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes.
Authors: Lipshultz SE, Miller TL, Lipsitz SR, Neuberg DS, Dahlberg SE, Colan SD, Silverman LB, Henkel JM, Franco VI, Cushman LL, Asselin BL, Clavell LA, Athale U, Michon B, Laverdière C, Schorin MA, Larsen E, Usmani N, Sallan SE, Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium
Source: Pediatrics, 2012 Dec;130(6), p. 1003-11.
EPub date: 2012 Nov 19.
PMID: 23166343
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Cranial irradiation as an additional risk factor for anthracycline cardiotoxicity in childhood cancer survivors: an analysis from the cardiac risk factors in childhood cancer survivors study.
Authors: Landy DC, Miller TL, Lipsitz SR, Lopez-Mitnik G, Hinkle AS, Constine LS, Adams MJ, Lipshultz SE
Source: Pediatr Cardiol, 2013 Apr;34(4), p. 826-34.
EPub date: 2012 Oct 19.
PMID: 23080542
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Cardiotoxicity in childhood cancer survivors: strategies for prevention and management.
Authors: Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE
Source: Future Cardiol, 2012 Jul;8(4), p. 647-70.
PMID: 22871201
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Cardiac failure 30 years after treatment containing anthracycline for childhood acute lymphoblastic leukemia.
Authors: Goldberg JM, Scully RE, Sallan SE, Lipshultz SE
Source: J Pediatr Hematol Oncol, 2012 Jul;34(5), p. 395-7.
PMID: 22584777
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Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy.
Authors: Lipshultz SE, Landy DC, Lopez-Mitnik G, Lipsitz SR, Hinkle AS, Constine LS, French CA, Rovitelli AM, Proukou C, Adams MJ, Miller TL
Source: J Clin Oncol, 2012 Apr 1;30(10), p. 1050-7.
EPub date: 2012 Mar 5.
PMID: 22393080
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Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes.
Authors: Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, Silverman LB, Colan SD, Neuberg DS, Dahlberg SE, Henkel JM, Asselin BL, Athale UH, Clavell LA, Laverdière C, Michon B, Schorin MA, Sallan SE
Source: J Clin Oncol, 2012 Apr 1;30(10), p. 1042-9.
EPub date: 2012 Feb 27.
PMID: 22370326
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Aggregating traditional cardiovascular disease risk factors to assess the cardiometabolic health of childhood cancer survivors: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study.
Authors: Landy DC, Miller TL, Lopez-Mitnik G, Lipsitz SR, Hinkle AS, Constine LS, French CA, Rovitelli AM, Adams MJ, Lipshultz SE
Source: Am Heart J, 2012 Feb;163(2), p. 295-301.e2.
PMID: 22305850
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Health effects of energy drinks on children, adolescents, and young adults.
Authors: Seifert SM, Schaechter JL, Hershorin ER, Lipshultz SE
Source: Pediatrics, 2011 Mar;127(3), p. 511-28.
EPub date: 2011 Feb 14.
PMID: 21321035
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Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial.
Authors: Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, Miller TL, Barry EV, Asselin BL, Athale U, Clavell LA, Larsen E, Moghrabi A, Samson Y, Michon B, Schorin MA, Cohen HJ, Neuberg DS, Orav EJ, Colan SD
Source: Lancet Oncol, 2010 Oct;11(10), p. 950-61.
EPub date: 2010 Sep 16.
PMID: 20850381
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Characteristics and determinants of adiposity in pediatric cancer survivors.
Authors: Miller TL, Lipsitz SR, Lopez-Mitnik G, Hinkle AS, Constine LS, Adams MJ, French C, Proukou C, Rovitelli A, Lipshultz SE
Source: Cancer Epidemiol Biomarkers Prev, 2010 Aug;19(8), p. 2013-22.
EPub date: 2010 Jul 20.
PMID: 20647396
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Clinical research directions in pediatric cardiology.
Authors: Lipshultz SE, Wilkinson JD, Messiah SE, Miller TL
Source: Curr Opin Pediatr, 2009 Oct;21(5), p. 585-93.
PMID: 19584723
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Anthracycline associated cardiotoxicity in survivors of childhood cancer.
Authors: Lipshultz SE, Alvarez JA, Scully RE
Source: Heart, 2008 Apr;94(4), p. 525-33.
PMID: 18347383
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