Evaluation of microRNAs as novel markers of cardiotoxicity in children undergoing anthracycline therapy for pediatric cancer

Study ID
STU 102011-096

Cancer Related

Healthy Volunteers

Study Sites

Beverly Kleiber

Principal Investigator
Naomi Winick


aim 1: This aim will be accomplished by performing a cross-sectional study of survivors of childhood cancer with and without an anthracycline-induced cardiomyopathy, as well as patients with a muscular dystrophy-associated cardiomyopathy. 15 childhood cancer survivors with previous anthracycline exposure and a cardiomyopathy attributable to anthracycline therapy will be identified from the Center for Cancer and Blood Disorder's cancer survivorship database and enrolled. an age-matched control cohort of childhood cancer survivors without anthracycline exposure will be identified and enrolled in a similar fashion. Finally, 15 young adults will be enrolled from the muscular dystrophy-associated cardiomyopathy clinic. Comprehensive plasma miR profiling will be performed utilizing a genome-wide miR microarray on a single blood sample from each patient. a group-wise comparison will be performed to identify miRs with altered expression that is specific to patients with anthracycline-induced cardiomyopathy. Profiling of a non-anthracycline cardiomyopathy group will allow us to hone in on miRs that specifically indicate anthracycline-mediated cardiac dysfunction versus those related to a cardiomyopathy in general.
aim 2: This aim will be completed by performing a prospective cohort study with 3 parallel cohorts, each containing 15-20 children for a total of 50 patients. The first 2 cohorts will include children undergoing anthracycline chemotherapy (n[?]30) and will be divided into cohorts one and two according to whether or not they have troponin evidence of cardiac injury following their anthracycline dose. The third cohort will include children without anthracycline exposure who are undergoing non-cardiotoxic chemotherapy (n[?]20). Candidate miR profiling will be performed in plasma samples from each child before and after a dose of anthracycline (Cohorts 1-2) or non-cardiotoxic chemotherapy (cohort 3). Samples will be obtained immediately prior to and 6, 12, and 24 hours following the chemotherapy dose.
Plasma samples will be screened by qRT-PCR for the miRs identified in aim 1, as well as a group of candidate miRs with known importance in cardiac response to stress and disease. This broader group of miRs will be assessed because miRs involved in the acute injury following anthracycline chemotherapy may be unique to those important in the chronic phase of anthracycline-induced cardiomyopathy. Further, these candidate miRs have been established as acute plasma markers of other forms of cardiac injury. all samples will be banked for a broader miR analysis by microarray, if necessary. Candidate miRs with altered expression following a chemotherapy dose will be identified and maximal miR fold-change quantified in each patient. additionally, cardiac troponins will be measured in all samples to identify patients with evidence of cardiac injury. after troponin measurements are performed, patients receiving anthracycline will be grouped into cohort 1 if they have one or more samples with a troponin elevation or cohort 2 if their samples are all troponin negative. a group-wise comparison between the two anthracycline cohorts and the control cohort will be performed to select miRs with specific dysregulation in children with troponin- indicated cardiac injury.
The expected duration of both cohorts is 2 years. accrual for both aims will begin in parallel and is expected to take place over 20 months. all study samples will be frozen as serum or plasma. Serum samples will be batched and assayed for troponins on a rolling schedule. Plasma samples will be stored until the completion of aim 1, which will inform some of the candidate miRs that are measured in these samples. after this point data collection and analysis will occur as the remaining samples are obtained.

Participant Eligibility

AIM 1:
1. Group 1: Childhood cancer survivors with anthracycline-induced cardiomyopathy (ACM)
o Survivor of childhood cancer
o Age 1-40 years
o Previous anthracycline exposure
o Echocardiogram findings of SF<28% or EF<50% or 15% decline in SF/ EF from baseline

2. Group 2: Childhood cancer survivor control group (without ACM):
o Survivor of childhood cancer
o Age 1-40 years, age-matched to group 1
o Exposed to non-cardiotoxic chemotherapy
3. Group 3: Muscular dystrophy-associated cardiomyopathy group:
o Age 16-40 years
o Diagnosed with a muscular dystrophy-associated cardiomyopathy
o Most recent echocardiogram or MRI measurements of SF<28% or EF<50%

AIM 2:
1) Cohorts 1 and 2: Children undergoing anthracycline chemotherapy:
o Child with cancer diagnosis requiring anthracycline chemotherapy
o Age 1 month to 20 years
o Prior anthracycline exposure:

* Limit of < 10 children with moderate dose exposure (between 85-224mg/m2)

* Remaining 10+ children must have high dose exposure (>225mg/m2)
o Scheduled to receive a future dose of anthracycline
2) Cohort 3: Children undergoing non-cardiotoxic chemotherapy (controls)
o Child with cancer diagnosis requiring non-cardiotoxic chemotherapy
o Age 1 month to 20 years
o Scheduled to receive a future dose of non-cardiotoxic chemotherapy