{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:22:01Z","timestamp":1793740921935,"version":"4.6.1"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018866","name":"Paula and Rodger Riney Foundation","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100018866","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100019591","name":"Harry T. 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Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.<\/jats:p>","DOI":"10.1172\/jci.insight.173646","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T10:22:17Z","timestamp":1713867737000},"source":"Crossref","is-referenced-by-count":8,"title":["Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia"],"prefix":"10.1172","volume":"9","author":[{"given":"Ola A.","family":"Elgamal","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA."},{"name":"Division of Hematology, Department of Internal Medicine, College of Medicine;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Fobare","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of 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