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Principal Investigator: Christopher James Clarke
Organization: STATE UNIVERSITY NEW YORK STONY BROOK
Fiscal Year: 2024
Award: $343,690
Funding agency: National Cancer Institute
ABSTRACT
Doxorubicin (Dox) is a mainstay in the treatment of many cancers yet its utility is limited by cardiovascular toxicity.
While multiple mechanisms underlying this cardiotoxicity have been proposed, strategies targeting these
pathways have had marginal effects or interfere with anti-cancer effects of the drug. Such concerns have
restricted the clinical use of dexrazoxane which is currently the only FDA-approved cardio-protective agent. As
cancer survival rates improve and more patients are exposed to Dox, there is a critical need for new strategies
to mitigate the cardiotoxicity without comprising its therapeutic efficacy. Bioactive sphingolipids (SLs), especially
ceramide (Cer), are well-established mediators of the chemotherapy stress response across diverse cancers.
While this increased interest in targeting SL metabolism to enhance chemotherapy responses, targeting SL
metabolism to reduce chemotoxicities is largely unexplored. We recently identified the Cer-generating enzyme
neutral sphingomyelinase-2 (nSMase2) as a primary Dox-regulated SL enzyme in breast cancer. Here, our
preliminary studies begin to implicate nSMase2-derived Cer in the Dox-induced DNA damage response of
cardiomyocytes (CMs) and show that in vivo loss of nSMase2 activity protects from the onset of Dox-induced
cardiac dysfunction and damage. Crucially, nSMase2 appears to be dispensable for the in vitro and in vivo anti-
cancer effects of Dox on breast cancer. Based on these data, the central hypothesis is that the nSMase2-
ceramide pathway is essential for Dox-induced cardiotoxicity but dispensable for Dox-induced anti-cancer
activity. We propose three specific aims: The first aim will establish Dox-induced activation of the nSMase2-
Cer pathway in cardiac cells and tissues combining in vitro and in vivo approaches to establish nSMase2
induction in CMs as a major pathway of Dox-induced Cer generation in the heart. The second aim will define
the role of the nSMase2-Cer pathway in mediating Dox-induced cardiotoxicity using in vitro and in vivo loss
of function approaches to establish nSMase2 in CMs as a mediator of Dox-induced CM cell death and cardiac
fibrosis. The third aim will establish the therapeutic potential of nSMase2 inhibitors as cardioprotective
agents that do not interfere with the anti-cancer activity of Dox using syngeneic xenograft models of breast
cancer to demonstrate the efficacy of nSMase2 inhibitors as cardioprotective agents that do not interfere with
Dox reduction of tumor growth and metastasis. Overall, these studies will provide novel insight into the
pathogenesis of Dox-induced cardiotoxicity and establish nSMase2 as a novel druggable target for
cardioprotection. This will provide a rational basis for the development of nSMase2 inhibitors as novel
cardioprotective agents.
Terms: <14-Hydroxydaunomycin><Adriamycine><Adverse effects><Anthracycline><Antioncogene Protein p53><Apoptosis><Apoptosis Pathway><Binding><Biological Markers><Body Tissues><Breast Cancer><Breast Cancer Model><Breast tumor model><Cancer Treatment><Cancers><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Stimulants><Cardiac Toxicity><Cardiocyte><Cardioprotective Agents><Cardiotonic Agents><Cardiotonic Drugs><Cardiotonics><Cardiotoxic><Cardiotoxicity><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Death><Cells><Cellular Tumor Antigen P53><Ceramides><Cessation of life><Chronic><Clinical><DNA Damage><DNA Injury><Data><Death><Development><Dexrazoxane><Doxorubicin><Doxorubicina><Drugs><Enzyme Gene><Enzymes><Exposure to><FDA approved><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Generations><Goals><Heart><Heart Injuries><Heart Muscle Cells><Heart Vascular><Heart myocyte><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Image><In Vitro><Induced Cardiomyocytes><Intermediary Metabolism><Intervention><Intervention Strategies><Laboratories><MALD-MS><MALDI><MALDI-MS><Malignant Breast Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Mediator><Medication><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Molecular Interaction><Myocardial Stimulants><Myocardial depression><Myocardial dysfunction><Neoplasm Metastasis><Oncoprotein p53><Oxidative Stress><P53><Pathogenesis><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Phosphoprotein P53><Phosphoprotein pp53><Positive Cardiac Inotropic Agents><Prevention><Programmed Cell Death><Protein TP53><Publishing><Regulation><Research><Role><Secondary Neoplasm><Secondary Tumor><Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization><Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization><Sphingolipids><Sphingomyelin Cholinephosphohydrolase><Sphingomyelin Cleaving Enzyme><Sphingomyelin Phosphodiesterase><Sphingomyelinase><Sphingomyelinase C><Survival Rate><TP53><TP53 gene><TRP53><Testing><Therapeutic><Tissues><Topoisomerase><Toxic effect><Toxicities><Treatment Efficacy><Treatment-related toxicity><Tumor Protein p53><Tumor Protein p53 Gene><Work><Xenograft Model><anti-cancer><anti-cancer therapy><anti-tumor effect><anticancer activity><antitumor effect><bio-markers><biologic marker><biological adaptation to stress><biomarker><cancer metastasis><cancer survival><cancer therapy><cancer-directed therapy><cardiac damage><cardiac dysfunction><cardiac fibrosis><cardiac injury><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cellular targeting><chemotherapy><circulatory system><clinical efficacy><coronary fibrosis><design><designing><developmental><drug/agent><druggable target><early onset><fibrotic heart><heart damage><heart dysfunction><heart fibrosis><icardiomyocytes><imaging><improved><in vivo><induced cardiac myocytes><inhibitor><insight><interest><intervention efficacy><interventional strategy><loss of function><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><matrix assisted laser desorption ionization><myocardial fibrosis><necrocytosis><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><pharmacologic><promoter><promotor><protein p53><reaction; crisis><response><response to therapy><response to treatment><side effect><social role><stress response><stress; reaction><therapeutic efficacy><therapeutic response><therapeutic toxicity><therapy associated toxicity><therapy efficacy><therapy related toxicity><therapy response><therapy toxicity><translational opportunities><translational potential><treatment response><treatment responsiveness><treatment toxicity><treatment-associated toxicity><tumor><tumor cell metastasis><tumor growth><xenograft transplant model><xenotransplant model>