Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.
Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.
In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.
David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.
The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.
Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.
The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.
The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.
Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.
Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.
The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.
Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.
“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.
“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”
