# Evaluation of myocardial targets to prevent anthracycline cardiotoxicity in children with Down Syndrome and Leukemia

> **NIH NIH R21** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $239,250

## Abstract

Children with Down syndrome (DS, trisomy 21) are at increased risk of developing certain cancers. Children with
DS have a reported 10-20 fold increased risk of developing acute myeloid leukemia (AML). Anthracycline-based
treatment regimens achieve good results in pediatric patients with DS and AML. However, children with AML
and DS are at high risk for treatment-related toxicities, including anthracycline-related cardiotoxicity. For
example, a report from the Children's Oncology Group documented anthracycline-related cardiomyopathy in
17.5 % of the patients with AML and DS. There is wide inter-individual variability in terms of susceptibility to
anthracycline-related cardiotoxicity, and there are no clinical treatments to prevent the development of
cardiotoxicity in children with AML and DS. For the past eight years, we have been conducting integrative studies
to identify myocardial determinants associated with the pathogenesis of anthracycline cardiotoxicity in individuals
with DS. We have shown that the expression of the chromosome 21 gene CBR1 is increased in DS myocardium
and results in higher synthesis rates of cardiotoxic anthracycline alcohol metabolites. This is important because
anthracycline alcohol metabolites resulting from high CBR1 activity are 40 times more cardiotoxic than parent
anthracyclines. These findings have contributed to support the rationale for dose reduction strategies in new
clinical protocols implemented by the Children's Oncology Group (trial: AAML0431. Blood, 2017). Novel
preliminary data suggest that the expression of DYRK1A, a key chromosome 21 gene associated with various
DS phenotypes, is altered in DS myocardium. Our data also suggest that the expressions of 1) embryonic
transcript variants of cardiac troponin TNNT2 and 2) the master splicing factor SRp55, are significantly increased
in myocardial tissue from individuals with DS. We propose that altered expression of the DYRK1A-SRp55-
TNNT2 pathway increases the susceptibility of DS myocardium to the cardiotoxic effects of anthracycline drugs.
Studies in Aim 1 will examine the role of the DYRK1A-SRp55-TNNT2 pathway during anthracycline cardiotoxicity
in a model of beating cardiomyocytes with trisomy 21. Studies in Aim 2 will examine whether combined
pharmacological inhibition of CBR1 and DYRK1A activities protects trisomic cardiomyocytes from the cardiotoxic
effects of anticancer anthracyclines. To further investigate determinants for drug induced cardiotoxicity in DS,
studies in Aim 3 will define the extent of genome-wide splicing alterations linked to the increased expression of
the master splicing factor SRp55 in myocardial tissue from persons with DS. These integrative studies will
provide new data for the design of pharmacological interventions to prevent the development of anthracycline
cardiotoxicity in pediatric patients with DS and AML.

## Key facts

- **NIH application ID:** 10022490
- **Project number:** 5R21CA245067-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Javier Guillermo Blanco
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $239,250
- **Award type:** 5
- **Project period:** 2019-09-23 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022490

## Citation

> US National Institutes of Health, RePORTER application 10022490, Evaluation of myocardial targets to prevent anthracycline cardiotoxicity in children with Down Syndrome and Leukemia (5R21CA245067-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10022490. Licensed CC0.

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