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|Ref Type||Journal Article|
|Authors||Sykes DB, Kfoury YS, Mercier FE, Wawer MJ, Law JM, Haynes MK, Lewis TA, Schajnovitz A, Jain E, Lee D, Meyer H, Pierce KA, Tolliday NJ, Waller A, Ferrara SJ, Eheim AL, Stoeckigt D, Maxcy KL, Cobert JM, Bachand J, Szekely BA, Mukherjee S, Sklar LA, Kotz JD, Clish CB, Sadreyev RI, Clemons PA, Janzer A, Schreiber SL, Scadden DT|
|Title||Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.|
|Date||2016 Sep 22|
|Abstract Text||While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Brequinar||DUP 785|DUP785|DUP-785|NSC368390|NSC-368390|NSC 368390|Bipenquinate||Brequinar (DUP 785) is a small molecule that selectively inhibits the activity of Dihydroorotate dehydrogenase (DHODH), potentially resulting in increased myeloid differentiation and decreased tumor burden (PMID: 27641501, PMID: 32525770).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||acute myeloid leukemia||not applicable||Brequinar||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, Brequinar treatment induced differentiation of acute myeloid leukemia cell lines in culture, reduced colony formation of tumor cells, decreased leukemic burden and leukemia initiating cells, and increased survival in syngeneic mouse models, and led to induced differentiation of tumor cells, inhibition of tumor growth, and increased survival in cell line xenograft models and a patient-derived xenograft (PDX) model (PMID: 27641501).||27641501|