{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:55:41Z","timestamp":1747184141041,"version":"3.40.5"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adverse drug reactions (ADRs) of targeted therapy drugs (TTDs) are frequently unexpected and long\u2010term toxicities detract from exceptional efficacy of new TTDs. In this proof\u2010of\u2010concept study, we explored how molecular causation involved in trastuzumab\u2010induced cardiotoxicity changes when trastuzumab was given in combination with doxorubicin, tamoxifen, paroxetine, or lapatinib. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases (such as UniProt and Reactome), for hypothesis generation regarding the underlying molecular mechanisms causing cardiotoxicity. Disproportionality analysis was used to assess the statistical relevance between adverse events of interest and molecular causation. Literature search was performed to compare the established hypotheses to published experimental findings. We found that the combination therapy of trastuzumab and doxorubicin may affect mitochondrial dysfunction in cardiomyocytes through different molecular pathways such as BCL\u2010X and PGC\u20101\u03b1 proteins, leading to a synergistic effect of cardiotoxicity. We found, on the other hand, that trastuzumab\u2010induced cardiotoxicity would be diminished by concomitant use of tamoxifen, paroxetine, and\/or lapatinib. Tamoxifen and paroxetine may cause less cardiotoxicity through an increase in antioxidant activities, such as glutathione conjugation. Lapatinib may decrease the apoptotic effects in cardiomyocytes by altering the effects of trastuzumab on BCL\u2010X proteins. This patient\u2010centered systems\u2010based approach provides, based on the trastuzumab\u2010induced ADR cardiotoxicity, an example of how to apply reverse translation to investigate ADRs at the molecular pathway and target level to understand the causality and prevalence during drug development of novel therapeutics.<\/jats:p>","DOI":"10.1111\/cts.13219","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T09:51:57Z","timestamp":1641894717000},"page":"1003-1013","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A case study of a patient\u2010centered reverse translational systems\u2010based approach to understand adverse event profiles in drug development"],"prefix":"10.1111","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-0735","authenticated-orcid":false,"given":"Sarah","family":"Kim","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gezim","family":"Lahu","sequence":"additional","affiliation":[{"name":"thinkQ2  Baar Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Majid","family":"Vakilynejad","sequence":"additional","affiliation":[{"name":"Takeda Oncology  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theodoros G.","family":"Soldatos","sequence":"additional","affiliation":[{"name":"Molecular Health GmbH  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David B.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Molecular Health GmbH  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence J.","family":"Lesko","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirjam N.","family":"Trame","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2106"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncponc1090"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804570200"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/1078155208090624"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208774"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701286104"},{"volume-title":"Type I and Type II Cardiomyopathy Classifications Are Complete Nonsense: PRO","year":"2018","author":"Witteles R.","key":"e_1_2_9_8_1"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djp440"},{"key":"e_1_2_9_10_1","unstructured":"NCCN Clinical Practice Guidelines in Oncology \u2010 Breast Cancer (Version 3.2020).2020.https:\/\/www.nccn.org\/patients\/. Accessed August 3 2020."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.repc.2012.11.002"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-007-9633-0"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x20144189"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414409200"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.09.029"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(02)01394-X"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-005-0075-7"},{"volume-title":"FDA Adverse Event Reporting System (FAERS) Public Dashboard","year":"2019","key":"e_1_2_9_18_1"},{"key":"e_1_2_9_19_1","unstructured":"MH Effect. Molecular Health GmbH 2019.https:\/\/www.molecularhealth.com\/us\/2017\/11\/17\/molecular\u2010health\u2010and\u2010fda\u2010us\/). Accessed August 3 2020."},{"volume-title":"Questions and Answers on FDA's Adverse Event Reporting System (FAERS)","year":"2018","key":"e_1_2_9_20_1"},{"key":"e_1_2_9_21_1","first-page":"7","volume-title":"Adverse Event Circumstances and the Case of Drug Interactions","author":"Soldatos TG","year":"2019"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ht7040037"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.677"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1742"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.08.066"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.3.255"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/hh1201.093159"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/hh1201.091794"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0789"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.7.12.6016"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2919"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.06.1167"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/abt\/tby003"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2015.03.005"},{"key":"e_1_2_9_35_1","unstructured":"Types of Breast Cancer: ER\u2010Positive HER2\u2010Positive and Triple Negative. WebMD.http:\/\/www.webmd.com\/breast\u2010cancer\/guide\/breast\u2010cancer\u2010types\u2010er\u2010positive\u2010her2\u2010positive. Accessed August 6 2020."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-1060-02"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdg483"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:BREA.0000032981.20384.c6"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c693"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2008.08040482"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.21.4437"},{"key":"e_1_2_9_42_1","unstructured":"MedDRA: Medical Dictionary for Regulatory Activities.https:\/\/www.meddra.org\/."},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2016.06.009"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1323"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12356"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/medicina55050149"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph12040141"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2074"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13219","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13219","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13219","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T13:59:00Z","timestamp":1692971940000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13219"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,11]]},"references-count":47,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1111\/cts.13219"],"URL":"https:\/\/doi.org\/10.1111\/cts.13219","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"type":"print","value":"1752-8054"},{"type":"electronic","value":"1752-8062"}],"subject":[],"published":{"date-parts":[[2022,1,11]]},"assertion":[{"value":"2021-08-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}