Why does the NAD pathway matter?

NAD is a helper molecule that plays a role in hundreds of chemical reactions, including the conversion of nutrients into usable cellular energy. The NAD salvage pathway is the recycling system cells use to maintain their NAD supply. Most cells can produce NAD through several different routes and switch between them when supply runs low.

The new data suggest MDS stem cells have lost that flexibility. They consume NAD faster than normal cells while depending on a single recycling route to keep up — a dependence the authors call an "energy addiction."

How serious is high-risk MDS?

Myelodysplastic syndromes are blood cancers that disrupt the bone marrow's ability to make healthy blood cells. Patients often develop severe anemia, suffer frequent infections, and need repeated transfusions. The condition occurs mainly in older adults, with an estimated 10,000 to 20,000 new U.S. cases diagnosed each year.

High-risk MDS can also progress to acute myeloid leukemia (AML), an aggressive leukemia that remains difficult to treat with current therapies. That risk is what makes finding the cancer-driving stem cells especially urgent.

Could drugs that block NAMPT help patients?

The new findings rest on laboratory experiments using patient-derived MDS cells and mouse models. No patients have yet received NAMPT-blocking drugs in this line of research.

Several compounds that inhibit NAMPT — including the experimental drug FK866 — have already been tested in early clinical trials for other cancers. The Colorado group plans to pursue similar clinical studies in MDS and related blood cancers.

The caveat is real. Cell and animal results do not always translate to human patients, and earlier NAMPT inhibitors have shown dose-limiting toxicities in past trials that could complicate dosing.

What's next?

Co-lead authors Pietras and Craig T. Jordan, PhD, will continue to study NAMPT inhibition in MDS samples and animal models. Sweta B. Patel, PhD, led the laboratory work, with collaborators including Angelo D'Alessandro, PhD, and Julie Reisz Haines, PhD, both at the University of Colorado Anschutz.

"Our goal is to identify approaches that make these complex diseases more treatable by finding the differences between cancer cells and normal cells," Pietras said. "If we can understand those differences, we can begin to develop therapies that are more precise and more effective for patients."

Funding came from the National Institutes of Health, the Edward P. Evans Foundation, and Blood Cancer United, along with other partners supporting blood cancer research.