New Research Identifies Unique Weaknesses in High-Risk Myelodysplastic Syndromes (MDS)

For people with high-risk myelodysplastic syndromes (MDS)  the treatment journey can be longer as they may have tried many different therapies that at some point stopped controlling the MDS. This could be due to how the mutations in high-risk MDS resist treatments. 

In a recent study, researchers wanted to better understand how MDS cells resist treatment. This can help develop more personalized treatments that allow healthy cells to remain functional and eliminate abnormal cells. 

What is high-risk myelodysplastic syndrome (MDS)?

MDS begins with abnormal changes in bone marrow stem cells. These stem cells, called hematopoietic stem and progenitor cells (HSPCs),  make healthy blood cells.

High-risk MDS is more aggressive and more likely to progress to acute leukemia. This is due to complex mutations that keep cancer cells alive and make them more resistant to therapies. The current standard treatment for high-risk MDS is azacitidine, a hypomethylating agent. However, azacitidine only works to treat about 30% of patients with high-risk MDS, and and responses often last less than two years.

Why are researchers studying metabolism in MDS stem cells?

Cancer cells often rewire how they produce and use energy. This study found that high-risk MDS stem cells have increased levels of metabolic proteins compared to healthy bone marrow stem cells.

Many of these proteins depend on a molecule called NAD (nicotinamide adenine dinucleotide). NAD helps cells:

• Produce energy.
• Maintain a healthy chemical balance.
• Support protein production.

The researchers found that MDS stem cells seem to rely heavily on NAD to maintain their activity and survive.

The nicotinamide salvage pathway: the power source of MDS cells

Nicotinamide is a form of vitamin B3 that cells use to make NAD. The cellular pathway that produces and recycles NAD is called the nicotinamide salvage pathway.  A key enzyme in this pathway is called NAMPT (nicotinamide phosphoribosyltransferase).

You can think of NAMPT as a recycling machine. It helps cells reuse nicotinamide to keep NAD levels steady. Without NAMPT, cells struggle to maintain enough NAD to function properly.

What happens when NAMPT is blocked in high-risk MDS?

The study used small-molecule inhibitors (OT82 and KPT-9274) to block NAMPT. When NAMPT was blocked:

• NAD levels dropped in both normal and MDS stem cells.
• Protein production was significantly reduced in MDS cells.
• Energy production and metabolic activity declined.
• MDS stem cells showed increased cell death.
• The ability of MDS stem cells to self-renew and form colonies was impaired.

Importantly, the metabolic disruption was much more harmful to MDS stem cells than to normal stem cells. This suggests that high-risk MDS cells are uniquely dependent on the nicotinamide salvage pathway.

How does NAMPT inhibition affect cancer cell energy and protein production?

When NAD levels fell, the researchers observed a strong decrease in protein synthesis. Protein synthesis is the process cells use to build proteins. Proteins are essential for cancer cell growth and survival.

They also found that blocking NAMPT disrupted how cancer cells processed glucose and glutamine. These are two major fuel sources for cells. Overall carbon flow through the cell slowed, showing widespread metabolic stress, meaning the cells needed to consume moore energy to perform their basic functions.

Without sufficient NAD, MDS stem cells could not maintain their energy systems or build the proteins they need to survive.

Can NAMPT inhibitors improve current MDS treatment?

One of the most encouraging findings was that NAMPT inhibition worked together with azacitidine. The combination increased apoptosis in MDS stem cells more than either treatment alone. Apoptosis is programmed cell death.

In mouse models, treatment with the NAMPT inhibitor OT82 significantly reduced disease burden after two weeks.

These results suggest that NAMPT inhibitors could potentially:

• Target the root MDS stem cells.
• Enhance the effect of standard therapy.
• Provide a new option for patients who do not respond to current treatments.

Why is this research important for patients with high-risk MDS?

This study identifies a unique vulnerability in high-risk MDS stem cells: their dependence on NAD production through the nicotinamide salvage pathway. By targeting NAMPT, researchers may be able to attack the disease at its source. This research is still very early, but the findings strongly support moving NAMPT inhibitors into early-phase (Phase 1/2) clinical trials to test safety and effectiveness in patients.

For people with high-risk MDS, who have tried many therapies that have not always succeeded in controlling their disease, research like this brings hope for more effective, longer-lasting treatment options. 

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Source: Targeting nicotinamide salvage pathway is a unique metabolic vulnerability of high-risk MDS stem cells