Hemopexin as an Early Biomarker of Anthracycline Cardiac Toxicity

PROJECT SUMMARY
This project seeks to contribute new insights into the role of heme metabolism in the pathogenesis of
anthracycline cardiac toxicity by leveraging studies in human patients and mouse models. The project will be
led by Aarti Asnani, MD, Cardiologist and Director of Cardio-Oncology at Beth Israel Deaconess Medical
Center (BIDMC) and Assistant Professor at Harvard Medical School (HMS). Dr. Asnani will collaborate with a
multidisciplinary team that will provide expertise in heme and cancer biology. Anthracyclines such as
doxorubicin (Dox) are very effective chemotherapies, but their use is limited by cardiac toxicity. Current risk
stratification and cardioprotective strategies are inadequate in patients treated with anthracyclines, largely
because they do not reflect the underlying molecular mechanisms of toxicity. To address this unmet need, we
used aptamer-based proteomics to measure over 1,300 plasma proteins in a discovery cohort of women
treated with anthracyclines for breast cancer. In addition to changes in proteins previously associated with
anthracycline cardiomyopathy, we identified hemopexin (HPX) as a new biomarker of cardiac toxicity, findings
that were validated in a second patient cohort using an ELISA-based assay. HPX is a 57-kDa circulating
glycoprotein synthesized in the liver that has a high binding affinity for the iron-containing molecule heme,
which is pro-oxidant and inflammatory. Upon binding to heme, HPX undergoes receptor-mediated endocytosis
via LRP-1, which is expressed by circulating macrophages and enables heme recycling in the splenic
reticuloendothelial system. This heme detoxification pathway is largely mediated by intracellular heme
oxygenase-1. Intracellular iron overload and macrophage-mediated inflammation have been described as key
molecular mechanisms of Dox cardiac toxicity, underscoring the biological plausibility of HPX as a biomarker in
this setting. Motivated by these human findings, we used a mouse model of chronic doxorubicin
cardiomyopathy to assess the mechanistic implications of HPX induction in anthracycline cardiac toxicity.
Based on our preliminary findings, we hypothesize that HPX is not only a biomarker of cardiac toxicity, but also
a cardioprotective pathway that is activated in response to anthracyclines. We will address this hypothesis in
the following aims: (1) To characterize the effects of HPX gain and loss-of-function on cardiac phenotypes in a
mouse model of chronic Dox cardiomyopathy; (2) To define the role of HPX in Dox cardiac toxicity through
integrative analyses of HPX kinetics and biodistribution, heme/iron metabolism, and chemical and genetic HO-
1 modulation; and (3) To assess the generalizability of blood heme, HPX, and other mechanistic biomarkers of
cardiac toxicity in diverse patient populations treated with anthracyclines. In addition to establishing HPX as a
biomarker of anthracycline cardiac toxicity, this line of investigation will clarify the role of heme metabolism in
cardiovascular disease more broadly. Modulation of HPX and associated pathways could ultimately represent
a new therapeutic strategy to protect the heart during chemotherapy.

Grant Number: 5R01HL163172-04
NIH Institute/Center: NIH
Principal Investigator: Aarti Asnani