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Prevention of Heart Failure induced by Doxorubicin with Early Administration of Dexrazoxane

Award Number: R01HL151993
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Prevention of Heart Failure induced by Doxorubicin with Early Administration of Dexrazoxane - Doxorubicin, an inhibitor of DNA topoisomerase 2a (Top2a), is routinely used in the treatment of breast cancer, sarcoma, and pediatric leukemia. Of the two topoisomerase 2 isozymes, Top2a is highly expressed in cancer cells and is required for cell division. However, adult cardiomyocytes express only topoisomerase 2b (Top2b), which is involved in DNA transcription, but not DNA replication. Long-term cancer survivors who were treated with doxorubicin and other anthracyclines often suffer from dose-dependent cardiotoxicity. Laboratory data showed that Top2a mediates doxorubicin’s tumoricidal activity, whereas Top2b mediates doxorubicin’s cardiotoxic effect. At present, dexrazoxane is the only FDA approved drug for cardio-protection. The cardio-protective effect of dexrazoxane is due to its ability to bind to the ATPase domain of Top2b to inhibit Top2b’s catalytic cycle. Currently, dexrazoxane is given concurrently with doxorubicin. Because dexrazoxane also binds to Top2a, it has the potential to interfere with doxorubicin’s tumoricidal effect. However, subclinical doxorubicin-induced cardiotoxicity is known to occur much earlier, perhaps at the initiation of doxorubicin therapy. Thus, dexrazoxane has limited clinical utility as specified by FDA’s approved indication. In preliminary studies, dexrazoxane induced an ubiquitin/ proteasome- mediated degradation of Top2b, but not Top2a. By administering dexrazoxane eight hours before doxorubicin, Top2b will be degraded to avoid cardiotoxicity, whereas Top2a will remain intact to preserve tumoricidal efficacy. Because the half-life of dexrazoxane is two hours, 93.75% of dexrazoxane will be eliminated eight hours (four half-lives) after administration. Indeed, dexrazoxane pre-treatment eight hours before doxorubicin provided complete protection against doxorubicin-induced cardiotoxicity in an animal model. In this proposal, this novel strategy will be tested in breast cancer patients prescribed doxorubicin- containing regimens. Two specific aims will be studied. Aim 1: To determine whether dexrazoxane given at a lower than FDA-approved dose is effective in degrading Top2b and the time-course of Top2b degradation in human volunteers. Aim 2: To test a mechanism-based hypothesis that early administration of dexrazoxane prevents doxorubicin-induced cardiotoxicity in non-metastatic, HER2- negative female breast cancer patients. HER2-negative, stage I-III female breast cancer patients will be enrolled in this prospective randomized, placebo-controlled, double-blind study. Patients will be monitored by cardiac MRI, Top2a, Top2b, and biomarkers before and after dexrazoxane/doxorubicin therapy. Tumor regression will be followed by oncologists clinically. Overall survival, event-free survival, and overall response (using response evaluation criteria in solid tumors -RECIST) will be collected to compare outcomes of cancer therapy with or without pre-treatment of dexrazoxane. Successful implementation of these trials will provide a novel and cost-effective strategy to prevent doxorubicin-induced cardiotoxicity.


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: 2024 ( Subtotal = $489,570 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	001	5	6/13/2024	NON-COMPETING CONTINUATION	$479,578
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	5	6/7/2024	NON-COMPETING CONTINUATION	$9,992
														Subtotal = $489,570

Issue Date FY: 2023 ( Subtotal = $710,737 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	4	7/6/2023	NON-COMPETING CONTINUATION	$710,737
														Subtotal = $710,737

Issue Date FY: 2022 ( Subtotal = $726,166 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	3	5/1/2022	NON-COMPETING CONTINUATION	$726,166
														Subtotal = $726,166

Issue Date FY: 2021 ( Subtotal = $727,686 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	003	2	6/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$763,778
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	001	2	4/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$727,686
2021	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	1	4/22/2021	NEW	$0
2021	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	002	1	6/28/2021	NEW	-$763,778
														Subtotal = $727,686

Issue Date FY: 2020 ( Subtotal = $763,778 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	1	6/8/2020	NEW	$763,778
														Subtotal = $763,778

Grand Total All Awards = $3,417,937

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Prevention of Heart Failure induced by Doxorubicin with Early Administration of Dexrazoxane

Award Number: R01HL151993

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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