The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia

摘要

The enzyme dihydroorotate dehydrogenase (DHODH) is essential for the de novo production of pyrimidines starting with the generation of uridine monophosphate (UMP), and small molecule inhibitors of DHODH are highly effective in vitro and in vivo in pre-clinical models of malignancy. DHODH is an unlikely cancer target, as it is ubiquitously expressed and is not known to be mutated or overexpressed in cancer. However, malignant cells seem to be more metabolically-dependent on de novo pyrimidine production, forming the potential basis of a therapeutic window. The use of DHODH inhibitors in solid tumor malignancies has been clinically disappointing. However, the use of DHODH inhibitors in the treatment of acute myeloid leukemia (AML) has been more recently shown to have both a cytotoxic and a pro-differentiation effect, making AML an attractive new disease indication. As of 2018, trials of DHODH inhibitors are underway, and will provide better insight into their potential utility in patients with hematologic malignancies.