Simple Compound Could Provide First New Therapy for Myeloid Leukemia in 40 Years

Harvard team makes potential breakthrough

Researchers at Massachusetts General Hospital and the Harvard Stem Cell Institute have identified a drug compound that arrests the progression of acute myeloid leukemia (AML), a bone marrow cancer that has not seen a new therapy in four decades. The new research was published in the journal Cell.

AML develops when blood stem cells and blood progenitor cells cannot differentiate into adult white blood cells, and instead get “frozen” in an immature state. Those immature cells take up space in the bone marrow and crowd out healthy cells, making it more difficult for the dwindling number of healthy blood cells to keep up with the body’s demands.

Current therapies are designed to kill cancer cells using toxic compounds that ultimately assault the body, destroy the immune system, and leave patients vulnerable to potentially deadly bacterial and fungal infections.

Chemotherapy typically used to treat younger people “is much too harsh for older patients,” which is problematic given that the average age of an AML patient is 67, said co-lead investigator Dr. David Scadden.

To find an alternative, the researchers used an approach that turned one of the most deadly subsets of the disease, acute promyelocytic leukemia, into one of the most treatable forms. Rather than killing the leukemia cells, the researchers searched for a compound that would encourage the cells to differentiate. When leukemia cells differentiate, they live for only a short time and die as part of their natural biology.

Mouse progenitor cells were engineered to glow green once they matured. The team, in collaboration with the Broad Institute of Harvard and the Massachusetts Institute of Technology, performed a functional screen with 330,000 compounds and found a dozen that were able to make the cells turn green, indicating that they forced the cells to differentiate. Of these promising compounds, 11 blocked a metabolic enzyme called DHODH, effectively forcing the cells into what the researchers called a period of fasting.

“Cancer cells are metabolically different from normal cells. Our results suggest normal cells can tolerate periods of fasting or starvation, while the cancer cells cannot. In this case, the fasting triggers a change,” said co-lead investigator Dr. David Sykes.

After 10 weeks of treatment with a known DHODH inhibitor, mice with AML and mice with human leukemia cells gained weight, were active, had fewer leukemia stem cells, and lived longer, indicating meaningful disease remission. Notably, no animal experienced disease progression during therapy. The researchers hope to test the inhibitor in a clinical trial.

“We need desperately to find new therapies,” not only for the 20,000 people diagnosed with AML every year, but for all cancers, Scadden said. “We think that an approach to overcome the differentiation blockade of cancer may be a strategy with broad application and one we should explore for other cancer types.”

Sources: Harvard Gazette; September 15, 2016; and Cell; September 15, 2016.