Dihydroorotate Dehydrogenase: An Unexpected Metabolic Vulnerability in Acute Myeloid Leukemia
David B. Sykes, MD, PhD, Massachusetts General Hospital, Harvard Medical School
Acute myeloid leukemia (AML) is a disease characterized by differentiation arrest: the inability of self-renewing progenitors to undergo their normal process of maturation. These immature leukemic “blasts” accumulate in the bone marrow, resulting in the anemia, thrombocytopenia, and infections that ultimately bring patients to medical attention. Despite a growing understanding of the genetic underpinnings of the disease, patients diagnosed with AML have an overall survival rate of only 25%. Furthermore, advances in diagnosis have not been accompanied by advances in treatment, and the chemotherapy standard of care remains unchanged since 1973. Our project sought to identify and to develop new differentiation therapy for the treatment of patients with AML. The ideal differentiation therapy would remove or overcome the blockade in maturation, and these mature cells would lose their leukemia stem cell activity. We established a new cellular model of differentiation arrest that permitted a high-throughput phenotypic screen of more than 330,000 small molecules. This led to the unexpected observation that inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) triggered myeloid differentiation. DHODH inhibitors were active in murine and human models of AML in vitro. Brequinar, a potent inhibitor of DHODH, was active in vivo, leading to differentiation, to a reduction in leukemia cell burden, and to a loss of leukemia-initiating cell activity across multiple models of AML. In addition, brequinar was well-tolerated in mice and spared the function of normal hematopoietic stem cells. DHDOH inhibition hopefully represents a much needed therapeutic avenue for the treatment of patients with AML.
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