{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:44:40Z","timestamp":1790138680128,"version":"4.0.1"},"reference-count":31,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T00:00:00Z","timestamp":1683158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer\u2010related mortality in children. Phosphoinositide 3\u2010kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3K\u03b4 and PI3K\u03b3, that is Food and Drug Administration (FDA) approved for the treatment of relapsed\/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient\u2010derived xenografts (PDXs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedures<\/jats:title><jats:p>Thirty PDXs were selected for a single mouse trial based on PI3K\u03b4 (<jats:italic>PIK3CD<\/jats:italic>) and PI3K\u03b3 (<jats:italic>PIK3CG<\/jats:italic>) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg\u2010<jats:italic>Prkdc<jats:sup>scid<\/jats:sup>IL2rg<jats:sup>tm1Wjl<\/jats:sup><\/jats:italic>\/SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45<jats:sup>+<\/jats:sup> cells (%huCD45<jats:sup>+<\/jats:sup>) in the peripheral blood. Treatment commenced when the %huCD45<jats:sup>+<\/jats:sup> reached greater than or equal to 1%, and events were predefined as %huCD45<jats:sup>+<\/jats:sup> greater than or equal to 25% or leukemia\u2010related morbidity. Duvelisib was administered per oral (50\u00a0mg\/kg, twice daily for 28\u00a0days). 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>PI3K\u03b4 and PI3K\u03b3 mRNA expression was significantly higher in B\u2010lineage than T\u2010lineage ALL PDXs (<jats:italic>p<\/jats:italic>\u2010values &lt;.0001). Duvelisib was well\u2010tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3K\u03b4 or PI3K\u03b3 expression or mutation status, nor was the in vivo response to duvelisib subtype dependent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Duvelisib demonstrated limited in vivo activity against ALL PDXs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.30398","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T11:41:15Z","timestamp":1683200475000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["In vivo activity of the dual PI3K\u03b4 and PI3K\u03b3 inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts"],"prefix":"10.1002","volume":"70","author":[{"given":"Joanna","family":"Randall","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 New South Wales 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 New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Watts","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 New South Wales Australia"}],"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 New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keira","family":"Hughes","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 New South Wales 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":"Stephen W.","family":"Erickson","sequence":"additional","affiliation":[{"name":"RTI International  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Pachter","sequence":"additional","affiliation":[{"name":"Verastem Oncology, Inc.  Needham Massachusetts 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; Health Centre for Childhood Cancer Research UNSW Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21654"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31669"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.11.002"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0216-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-366203"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3860"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20020412"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00064"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-020-05435-1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26135"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00099"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.4.2236"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.09.017"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph12020069"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0954-x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.11.4100"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-08-2911"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27765"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.071"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-0122"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1958.10501452"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21078"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.105"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.167601"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.80"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071724"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.25105"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-05-707653"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.0018"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200725"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70114-5"}],"container-title":["Pediatric Blood &amp; 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