{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:06:28Z","timestamp":1753869988098,"version":"3.41.2"},"reference-count":39,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"FP7 Industry Academia Pathways and Partnerships Marie Curie Award","award":["251528"],"award-info":[{"award-number":["251528"]}]},{"name":"Horizon 2020 research and innovation programme \u201cColossus\u201d","award":["754923"],"award-info":[{"award-number":["754923"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteomics Clinical Apps"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>The tyrosine kinase inhibitor (TKI) sunitinib is a multi\u2010targeted agent approved across multiple cancer indications. Nevertheless, since approval, data has emerged to describe a worrisome side effect profile including hypertension, hand\u2010foot syndrome, fatigue, diarrhea, mucositis, proteinuria, and (rarely) congestive heart failure. It has been hypothesized that the observed multi\u2010parameter toxicity profile is related to \u201con\u2010target\u201d kinase inhibition in \u201coff\u2010target\u201d tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Design<\/jats:title><jats:p>To interrogate off\u2010target effects in pre\u2010clinical studies, a reverse phase protein array (RPPA) approach is employed. Mice are treated with sunitinib (40\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>) for 4 weeks, following which critical organs are removed. The Zeptosens RPPA platform is employed for protein expression analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Differentially expressed proteins associated with damage and\/or stress are found in the majority of organs from treated animals. Proteins differentially expressed in the heart are associated with myocardial hypertrophy, ischaemia\/reperfusion, and hypoxia. However, hypertrophy is not evidenced on histology. Mild proteinuria is observed; however, no changes in renal glomerular structure are visible via electron microscopy. In skin, proteins associated with cutaneous inflammation, keratinocyte hyper\u2010proliferation, and increased inflammatory response are differentially expressed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Clinical Relevance<\/jats:title><jats:p>It is posited that pre\u2010clinical implementation of a combined histopathological\/RPPA approach provides a sensitive method to mechanistically elucidate the early manifestation of TKI on\u2010target\/organ off\u2010target toxicities.<\/jats:p><\/jats:sec>","DOI":"10.1002\/prca.201800159","type":"journal-article","created":{"date-parts":[[2019,2,15]],"date-time":"2019-02-15T13:08:59Z","timestamp":1550236139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre\u2010Clinical Detection of Off\u2010Target Toxicities Associated with Sunitinib Malate"],"prefix":"10.1002","volume":"13","author":[{"given":"Alice C.","family":"O'Farrell","sequence":"first","affiliation":[{"name":"RCSI Centre for Systems Medicine Department of Physiology &amp; Medical Physics Royal College of Surgeons in Ireland  Dublin 2 D02 HX03 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2118-6345","authenticated-orcid":false,"given":"Ian S.","family":"Miller","sequence":"additional","affiliation":[{"name":"RCSI Centre for Systems Medicine Department of Physiology &amp; Medical Physics Royal College of Surgeons in Ireland  Dublin 2 D02 HX03 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rhys","family":"Evans","sequence":"additional","affiliation":[{"name":"RCSI Centre for Systems Medicine Department of Physiology &amp; Medical Physics Royal College of Surgeons in Ireland  Dublin 2 D02 HX03 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Alamanou","sequence":"additional","affiliation":[{"name":"OncoMark Ltd. 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