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Slow metabolism gives leukemia staying power

U. ROCHESTER (US) — A super slow metabolism may be one reason acute myeloid leukemia is so hard to cure.

The slower metabolism protects leukemia cells in many important ways and allows them to survive better, but researchers have found an experimental drug tailored to this unique metabolic status and have begun testing its ability to attack the disease, which is one of the most aggressive of all cancers.

“Targeting metabolism of leukemia stem cells is a unique approach that we believe has the potential to be broadly applied to several forms of leukemia,” says Craig Jordan, professor at the James P. Wilmot Cancer Center at the University of Rochester Medical Center.

“An exciting part of our work is that because we’ve identified drugs that are being developed for clinical use, we hope there is significant potential to improve the care of leukemia patients relatively soon.”

When the team discovered that the metabolism of leukemia stem cells was so different from the rest of the tumor cells, they focused their efforts on exactly how that process works, says Eleni Lagadinou, a post-doctoral fellow in Jordan’s lab and lead investigator of the study published in the journal Cell Stem Cell.

They found that leukemia stem cells generate all the energy they need in a cellular powerhouse called the mitochondrion, by way of a single process, known as oxidative phosphorylation. In contrast, other cancer cells and normal stem cells also rely on a second fuel source, known as glycolysis, to generate energy.

With this new information, researchers then explored the pathways involved in oxidative phophorylation, with an eye toward finding an Achilles’ heel to stop the process. They discovered that an important gene, BCL-2, is elevated and central to leukemia stem cell energy production.

The team also knew that drugs to inhibit BCL-2 are in various stages of development in the pharmaceutical industry. The researchers found two such compounds and tested them in human leukemia specimens. Their findings showed the drugs preferentially killed inactive and metabolically slower leukemia stem cells.
Leukemia is known for its ability to lie dormant for long periods, despite treatment, but then suddenly begin another assault.

“This treatment shows promise toward a dormant leukemic stem cell subpopulation that is relatively untouched by conventional drugs,” Lagadinou says. “It’s also important to note that normal cells were not harmed by the compounds, because they can use alternative pathways to generate energy.”

Without the toxicity to healthy cells, researchers hope they can target the disease during periods of remission, when mopping up residual leukemia is essential.

Acute myelogenous leukemia is most common in adults and the most difficult to treat, in part because it affects immature cells. Nearly 50,000 new cases are diagnosed each year, with about half resulting in death.

Investigators have learned during the past decade that many therapies were not designed to kill the root of leukemia, the so called “leukemia stem cells,” and therefore never truly eliminate the disease.

In fact, even the most modern cancer treatments were developed under the assumption that all cancer metabolism relies on glycolysis as a fuel source. This makes the new study—and the discovery that oxidative phosphorylation is the single fuel source for leukemia stem cells—all  the more relevant for suggesting new and improved treatments, Jordan says.

The research received support from the Leukemia and Lymphoma Society, National Institutes of Health, and New York State Stem Cell Science.

Source: University of Rochester

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