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Simple, Cheap Method Could Improve Stem Cell Transplant

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Anette Breindl
Science Editor

Scientists have discovered that nonsteroidal anti-inflammatory drugs (NSAIDs) can both mobilize blood-forming stem cells to leave the bone marrow and enter general circulation to be harvested for transplantation, and can engraft more easily when they are transplanted.

"The real take-home bottom line is that if you want more stem cells, take an aspirin," Louis Pelus, of the Indiana University School of Medicine, told BioWorld Today. And although the actual drug he and his team propose using is not aspirin, conceptually, "that's how simple this is."

The findings could improve the harvesting of stem cells for bone marrow transplants, which, Pelus explained, "are not, for the most part, done using bone marrow anymore." Instead, patients receive a "stem cell mobilizing" drug, Neupogen (filgrastim, Amgen Inc.), which coaxes stem cells out of their niche in the bone marrow and into the bloodstream, where they can be harvested and then transplanted.

Some people, however – both patients who are donating stem cells for an autologous transplant and bone marrow donors – do not respond well to Neupogen. Such patients can currently be treated with a second drug. But at $28,000 per course, that drug adds significantly to the price tag of a bone marrow transplant.

The price tag of the treatment that Pelus and his colleagues are suggesting as an alternative is less than a dollar.

With their work, Pelus, first author Jonathan Hoggatt and their colleagues followed up on previous studies by Pelus on the effects of prostaglandins, the signaling molecules whose synthesis is inhibited by NSAIDs that target Cox enzymes.

Studies had suggested decades ago that prostaglandins could affect stem cells, "but we had no way to prove that at the time," Pelus explained. But with advances in technology came the ability to show that inhibiting prostaglandin E2 increased the levels of stem cells, as well as levels of progenitor cells, in the blood.

The mechanism, however, was unexpected. Rather than acting through a cytokine receptor that is a well-known target of prostaglandins, treatment with NSAIDs led to a decrease in osteopontin levels that are produced by osteoblasts.

As a net result, stem cells "become untethered" in the bone marrow and go into the bloodstream in greater numbers. And when such cells were transplanted, they also engrafted into the recipients more rapidly – perhaps because there were more of them, or perhaps because they were of higher quality. "We don't have all the answers as to why yet," Pelus said. "But we do know that this happens." The results were published in the March 14, 2013, issue of Nature.

It is on some levels astonishing that the effect of NSAIDs, which are both in widespread use and have been scrutinized in great detail due to unexpected problems with drugs such as Vioxx and Bextra, could go undetected for decades.

Pelus attributed the oversight to several reasons. For one, the rise in stem cells is small in absolute terms. Stem cells are rare even in the bone marrow, and rarer still in the blood. For another, the mobilized stem cells do not lead to an increase in the number of blood cells, which is what clinicians monitor if they have reason to believe that a treatment might affect blood stem cells. Finally, the effects of NSAIDS on blood stem cells are transient.

"After a few days, the system resets itself," Pelus said, meaning that chronic treatment with NSAIDs does not lead to a chronic increase of stem cell levels in the blood.

For now, the findings are preclinical. But Pelus was optimistic that they will translate into the clinic, for two reasons.

One is the sheer simplicity of the approach. "It is very hard to translate complex findings into the clinic. This is simple," he said. "It's rooted in very solid biology, but it's simple."

Another is that his team has conducted experiments in baboons, and showed that there, too, NSAID treatment increased the number of stem cells that could be harvested if it was added to Neupogen.

Pelus and his team intend to start a clinical trial "very soon" that adds an NSAID to the drug regimen that is used for bone marrow transplant. Because they increase the risk of belling, NSAIDs are normally contraindicated before a bone marrow transplant, but the drug that the researchers propose using, meloxicam, does not affect platelet aggregation as much as other drugs in this class – "it has a good profile for this indication."

The impending trial "is not going to be very extensive initially, because we have to get funding," he said. His team has just submitted a grant for such funding, which is not for the treatment itself, since the bone marrow procedure is the standard of care and the dollar that the NSAID adds is trivial.

"What we need money for is accessory science," Pelus said – primarily, to see whether the interplay of NSAID and Neupogen has the same biological consequences in humans as it does in mice.

That science, he added, is not critical from a clinical point of view. For a clinical regimen to be successful, "you really only need to know that it's working, not how it works. But it's a loss to not follow up on the science."