{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:44:38Z","timestamp":1790138678058,"version":"4.0.1"},"reference-count":47,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:00:00Z","timestamp":1687219200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA199000"],"award-info":[{"award-number":["CA199000"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA199222"],"award-info":[{"award-number":["CA199222"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA263963"],"award-info":[{"award-number":["CA263963"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high\u2010risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B\u2010lineage ALL (B\u2010ALL). Activating mutations or overexpression of Fms\u2010related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK\u2010659 (mivavotinib) is a dual SYK\/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK\u2010659 against pediatric ALL patient\u2010derived xenografts (PDXs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>SYK<\/jats:italic> and <jats:italic>FLT3<\/jats:italic>\u00a0mRNA expression was quantified by RNA\u2010seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45<jats:sup>+<\/jats:sup> cells (%huCD45<jats:sup>+<\/jats:sup>) in the peripheral blood. TAK\u2010659 was administered per oral at 60\u00a0mg\/kg daily for 21 days. Events were defined as %huCD45<jats:sup>+<\/jats:sup> \u2265 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event\u2010free survival and stringent objective response measures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>FLT3 and SYK mRNA expression was significantly higher in B\u2010lineage compared with T\u2010lineage PDXs. TAK\u2010659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45<jats:sup>+<\/jats:sup> was significantly reduced in five out of eight PDXs in TAK\u2010659\u2010treated mice compared with vehicle controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>TAK\u2010659 exhibited low to moderate single\u2010agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.30503","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T02:17:41Z","timestamp":1687313861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["In vivo activity of the dual SYK\/FLT3 inhibitor TAK\u2010659 against pediatric acute lymphoblastic leukemia xenografts"],"prefix":"10.1002","volume":"70","author":[{"given":"Keira","family":"Hughes","sequence":"first","affiliation":[{"name":"Children's Cancer Institute Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, Centre for Childhood Cancer Research, UNSW Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Evans","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, Centre for Childhood Cancer Research, UNSW Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6576-1319","authenticated-orcid":false,"given":"Eric J.","family":"Earley","sequence":"additional","affiliation":[{"name":"RTI International Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, Centre for Childhood Cancer Research, UNSW Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W.","family":"Erickson","sequence":"additional","affiliation":[{"name":"RTI International Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Stearns","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek M.","family":"Philip","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven B.","family":"Neuhauser","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Chuang","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily L.","family":"Jocoy","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol J.","family":"Bult","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly A.","family":"Teicher","sequence":"additional","affiliation":[{"name":"National Cancer Institute Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9880-9876","authenticated-orcid":false,"given":"Malcolm A.","family":"Smith","sequence":"additional","affiliation":[{"name":"National Cancer Institute Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3436-9071","authenticated-orcid":false,"given":"Richard B.","family":"Lock","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; 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