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Hemopexin as an Early Biomarker of Anthracycline Cardiac Toxicity

Award Number: R01HL163172
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $581,874 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	3/28/2025	NON-COMPETING CONTINUATION	$581,874
														Subtotal = $581,874

Issue Date FY: 2024 ( Subtotal = $633,596 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$51,722
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	4/1/2024	NON-COMPETING CONTINUATION	$581,874
														Subtotal = $633,596

Issue Date FY: 2023 ( Subtotal = $654,307 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	3/31/2023	NON-COMPETING CONTINUATION	$654,307
														Subtotal = $654,307

Issue Date FY: 2022 ( Subtotal = $672,532 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	3/16/2022	NEW	$672,532
														Subtotal = $672,532

Grand Total All Awards = $2,542,309

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Hemopexin as an Early Biomarker of Anthracycline Cardiac Toxicity

Award Number: R01HL163172

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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