Researcher Stories

Drug-induced Cardiotoxicity

Interindividual variability in drug-induced cardiotoxicity risk

Javier G. Blanco, PhD, Associate Professor, University at Buffalo, The State University of New York

Clinical evidence suggests that patients with leukemia and Down syndrome are at increased risk for drug-induced cardiotoxicity, increasing the need for safer therapeutic options for specific patient populations.  Specifically, the anthracyclines, doxorubicin and daunorubicin, used for the chemotherapy of a variety of cancers leads to the development of cardiotoxicity in some patients.  Understanding the risk factors associated with drug-induced cardiotoxicity is essential to improve patient therapies.

blanco lab pic

blanco lab pic

The Blanco lab, from left to right, Erik Hefti, Adolfo Quiñones, Javier Blanco, Daniel Ferguson, Elizabeth Patt, and James Hill. Photo taken by Olivia M. Campagne.

Javier Blanco, PhD, an associate professor in the Department of Pharmaceutical Sciences at University at Buffalo, The State University of New York, and his team are studying how specific genetic and epigenetic factors contribute to the variable pharmacodynamics of anthracyclines in relevant patient populations. These projects are providing essential data for the design of: 1) less toxic anti-cancer therapies, and 2) strategies for the identification of patients “at risk” for anthracycline-related cardiotoxicity.  These studies include work in heart tissue samples from donors with and without Down syndrome to identify determinants for drug-induced cardiotoxicity in cancer patients with Down syndrome.

“The scarcity of good quality tissue samples from donors with Down syndrome (DS) is hampering biomedical research on fundamental issues concerning the pathobiology of DS. NDRI has been crucial to our research efforts by providing us with invaluable samples. We would like to express our deepest appreciation to donors and their families.”      

Dr. Blanco’s research efforts are aimed at improving cancer chemotherapy for pediatric and adult patients.  His group’s work is funded by the NIH and their translational research extends to work with colleagues from the Roswell Park Cancer Institute (RPCI), Buffalo General Hospital, and the Children’s Oncology Group (COG) to test whether genetic and epigenetic variants in specific gene networks impact the risk of cardiotoxicity in cancer survivors.

Recent Publications

Hefti E, Bard J, and Blanco JG. 2017. Analysis of heteroplasmic variants in the cardiac mitochondrial genome of individuals with Down syndrome. Human Mutation 38(1): 48-54. PMID:  27594409.

Hoefer CC, Hageman-Blair R, and Blanco JG. 2016. Development of a CART model to predict the synthesis of cardiotoxic daunorubicinol in heart tissue samples from donors with and without Down syndrome. Journal of Pharmaceutical Science 105(6):2005-8. PMID: 27112290.

Wang X, Sun CL, Quiñones-Lombraña A, Singh P, Landier W, Hageman L, Mather M, Rotter JI, Taylor KD, Chen YI, Armenian SH, Winick N, Ginsberg JP, Neglia JP, Oeffinger KC, Castellino SM, Dreyer ZE, Hudson MM, Robison LL, Blanco JG, Bhatia S. 2016. CELF4 variant and anthracycline-related cardiomyopathy: a Children's Oncology Group genome-wide association study. Journal of Clinical Oncology 34(8):863-70. PMID: 26811534.

Hoefer CC, Quiñones-Lombraña A, Blair RH, Blanco JG. 2016. Role of DNA methylation on the expression of the anthracycline metabolizing enzyme AKR7A2 in human heart. Cardiovascular Toxicology 16(2):182-92. PMID: 25962911.

Hefti E, Quiñones-Lombraña A, Redzematovic A, Hui J, Blanco JG. 2016. Analysis of mtDNA, miR-155 and BACH1 expression in hearts from donors with and without Down syndrome. Mitochondrial DNA 27(2):896-903. PMID: 24938108.

Quiñones-Lombraña A, Blanco JG. 2015. Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM). Biochimica et Biophysica Acta 185(7):1420-7. PubMed PMID: 25869329.

Quiñones-Lombraña A, Ferguson D, Hageman Blair R, Kalabus JL, Redzematovic A, Blanco JG. 2014. Interindividual variability in the cardiac expression of anthracycline reductases in donors with and without Down syndrome. Pharmaceutical Research 31(7):1644-55. PMID: 24562808.

Wang X, Liu W, Sun CL, Armenian SH, Hakonarson H, Hageman L, Ding Y, Landier W, Blanco JG, Chen L, Quiñones A, Ferguson D, Winick N, Ginsberg JP, Keller F, Neglia JP, Desai S, Sklar CA, Castellino SM, Cherrick I, Dreyer ZE, Hudson MM, Robison LL, Yasui Y, Relling MV, Bhatia S. 2014. Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group. Journal of Clinical Oncology 32(7):647-53. PMID: 24470002.

Kalabus JL, Sanborn CC, Jamil RG, Cheng Q, Blanco JG. 2010. Expression of the anthracycline-metabolizing enzyme carbonyl reductase 1 in hearts from donors with Down syndrome. Drug Metabolism and Disposition 38(12):2096-9. PMID: 20729274.

 

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