Candidate serum biomarkers of doxorubicin-induced cardiotoxicity in pediatric acute lymphoblastic leukemia assessed by nanoparticle-capture mass spectrometry.

Abstract

9528 Background: To identify low-molecular weight and abundance candidate biomarker proteins of doxorubicin cardiotoxicity in childhood ALL by innovative nanoparticle capture-mass spectrometry (MS). Comparison to elevated serum cardiac troponin T (cTnT), a validated marker of doxorubicin myocardial injury, is made. Methods: 40 sera from 14 children with ALL receiving doxorubicin were assessed: 20 were cTnT- (<0.01 ng/mL, n=8) and 20 were cTnT+, n=6. A hydrogel core-shelled nanoparticle containing acid black dye as a protein-binding agent captured, concentrated, and isolated candidate biomarker proteins from high-abundance blood proteins. High-resolution MS analyzed the nanoparticle- captured archive and identified differentially expressed serum proteins in children with detectable (+) and non-detectable (−) cTnT. Results: 226 proteins achieved a 50% difference in spectral counts between the cTnT- and cTnT+ groups. 47 proteins had significant differential expression (P<0.1) between the two groups. A more stringent statistical filtering (P< 0.007) yielded several differentially abundant proteins associated with myocardial injury. The peptide-spectra assignments from a SEQUEST search were verified manually and included three potentially differentially abundant proteins; cardiac actin, procollagen C endopeptidase enhancer, and periostin. Nanoparticle-MS is able to uncover these candidate protein biomarkers previously implicated in cardiac dysfunction, remodeling, fibrosis, and hypertrophy. Conclusions: Candidate serum biomarkers may potentially increase the predictive value of conventional markers such as cTnT for earlier detection of cardiac damage. Identifying heart-derived tissue proteins associated with myocardial injury, which can be detected before marked elevations in cTnT, would have profound implications on the earlier detection and clinical monitoring for doxorubicin cardiotoxicity before irreversible damage and loss of cardiomyocytes occurs. Additional studies evaluating the efficacy of nanoparticle-MS may advance this novel diagnostic approach to trigger cardiac evaluation and protection. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ceres Nano Sciences, LLC, Theranostics Health Ceres Nano Sciences, LLC, Theranostics Health George Mason University