New Treatments May be on the Horizon for Aggressive Leukemia

DHODH inhibitor caused a reduction in leukemic stem cells and long-term remission in mice.

A promising new approach for the treatment of acute myeloid leukemia (AML) has been found, according to a study published in Cell.

AML occurs when the normal process by which myeloid stem cells differentiate into a specific group of mature white blood cells is stopped, causing proliferation of immature, abnormal cells that suppress the development of normal blood cells.

“AML is a devastating form of cancer; the 5-year survival rate is only 30%, and it is even worse for the older patients who have a higher risk of developing the disease,” said senior study author David Scadden, MD. “New therapies for AML are extremely limited — we are still using the protocols developed back in the 1970s – so we desperately need to find new treatments.”

Previous studies have shown that the expression of transcription factor HoxA9 is actually maintained in 70% of AML patients. However, there are no HoxA9 inhibitors that have been identified, so researchers instead used a novel approach to screen potential inhibitors based on whether they could overcome the differentiation blockade characteristic of AML cells.

Through the study, researchers were able to identify a crucial dysfunction in blood cell development that underlies AML. By inhibiting the action of a specific enzyme it prompted the differentiation of leukemic cells, reducing the amount, and decreasing their ability to promote cancer.

For the study, researchers created a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to glow green once they reached maturity. More than 330,000 small molecules were screened to identify which would produce the green signal in the cells, indicating that the HoxA9-induced differentiation blockade had been overcome, according to the study.

The results of the screening showed only 12 compounds that produced the desired result, 11 of which were found to act by suppressing a metabolic enzyme called DHODH, which was not previously known to have a role in myeloid differentiation. Upon further examination, researchers found that inhibiting DHODH could induce differentiation in both mouse and human AML cells.

Next, researchers tested a known DHODH inhibitor in several of their mouse models of AML, and identified a dosing schedule that reduced the levels of leukemia cells and prolonged survival. Additionally, there was no evidence of the adverse effects of traditional chemotherapy.

Although only 6 weeks of treatment was not able to prevent eventual relapse, treatment for up to 10 weeks appeared to result in long-term remission, which included the reduction of leukemia stem cells that can lead to relapse. Similar results were seen in mice.

“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,” Scadden said. “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.”