Dr. Sykes and Dr. Scadden collaborate in the lab
Dr. Sykes and Dr. Scadden collaborate in the lab

How do you stop a deadly case of arrested development?

That question prompted a six-year pursuit into the mechanisms underlying acute myeloid leukemia (AML) for David Sykes, MD, PhD, David Scadden, MD, and a team of collaborators from Massachusetts General Hospital, the Broad Institute, Bayer Pharma and the University of New Mexico.

The results of that work—which identifies how the normal process of white blood cell maturation is disrupted in AML and points to a potential treatment target—was published in Cell in the fall of 2016.

In a recent interview, Sykes described the project as a true team effort. “This is a paper that has 30 authors and a whole group of people in the acknowledgements that really could have been authors.”

Teamwork was key during a long and challenging process of discovery that started with 330,000 potential compounds and ended with the identification of a promising new treatment strategy based on a drug that had been previously tested in cancer patients but is not currently in use.

There are now several pharmaceutical companies working to develop similar drugs, and the first clinical trials for AML patients could start next year.


Acute myeloid leukemia (AML) is a highly fatal form of blood cancer that occurs when the natural birth, maturation and death cycle of myeloid cells (a type of white blood cell) is interrupted, leading to an overpopulation of immature cells in the bloodstream. Only 30% of adults diagnosed with AML survive past five years.

Sykes explained that humans develop mature myeloid cells from immature progenitors or “starter cells” in the bone marrow at an incredible rate (approximately 150,000 cells per second). Under normal circumstances, these cells have a very limited lifespan—after differentiating into mature cells, they die off in a period of only 1-2 days.

“The body maintains this perfect balance, counting on the fact that it is making the same number of new cells to replace the ones that die off,” Sykes explained.

In AML, however, this cycle is interrupted. The immature cells no longer mature and die off, but stay in their immature form and continue to divide, filling the bone marrow and interfering with regular blood cell production.

“The cells themselves are not malicious, they just take up space,” Sykes explained. “They are kind of like teenagers in the mall, hanging out and causing trouble. If they would just grow up, they wouldn’t cause trouble any more. But they are just hanging out in the food court, filling up space and crowding out the regular customers.”

Undifferentiated and differentiated myeloid cells

This image provided by David Sykes, MD, PhD, shows undifferentiated myeloid cells on the left, differentiated (or mature) cells on the right.

The challenge for Sykes and his collaborators was to figure out what was taking place on the molecular level to prevent myeloid cells from maturing, and to see if they could find a way to override it.

The project was one of many stages, from an idea conceived in 2010, to the development of a new screening system, to an extensive and time-consuming high-throughput screen in New Mexico, to medicinal chemistry efforts by Stuart Schreiber, PhD, at the Broad Institute, and a true collaboration between academia and industry to complete the pre-clinical studies.


To start the process, Sykes, Scadden and their collaborators devised a system for collecting and preserving immature myeloid cells. They then screened the cells against a library of 330,000 chemical compounds to see if any of the compounds would prompt cells to mature.

The screening process presented its own set of challenges. Testing for each compound required a four-day incubation period, whereas a typical drug screen incubation ranges from a few to 24 hours. The only facility with the capacity to conduct the screening was the Center for Molecular Discovery at the University of New Mexico, which meant Sykes couldn’t be on hand to oversee the day-to-day process.

Thus one of the unsung heroes of the project was Mark Haynes, PhD, a researcher at the New Mexico screening facility.

“When you think about 330,000 molecules, arrayed on 1,200 plates, each with 330 molecules, and Mark put each one of those plates on four machines by hand over the course of many months. There were days when everything failed and had to be repeated. I went out to New Mexico four times to help set everything up and troubleshoot, but it was really a labor of love by Mark.”

Out of 330,000 molecules tested, the team identified 12 candidates that prompted the stem cells to mature. Sykes then brought those molecules back to the team in Dr. Schreiber’s chemistry lab at the Broad Institute in Cambridge, where they narrowed the pool of compounds down to two.

Further investigation revealed that these compounds were inhibiting an enzyme called DHODH. Sykes explained that DHODH is in every cell of the body, and controls the fundamental synthesis of uridine. Uridine is a fundamental building block of RNA and DNA and carries metabolites around the cell. “As you can imagine, you wouldn’t think that you could interrupt that building block in normal cells and get away with it.”

Group in lab

Pictured, from left, are study c-authors  David Sykes, MD, PhD, Youmna Kfoury, PhD, Francois Mercier, MD, and David Scadden, MD, all from the Center for Regenerative Medicine at Massachusetts General Hospital.


The true excitement came when the team discovered there was already a drug targeting DHODH that had been developed by DuPont pharmaceuticals in the 1980s and had been previously studied in humans.

The drug, called Brequinar, had been discontinued because it was not effective in treating cancer patients with solid tumors. It was now long off patent, so it was possible for the team to start testing it as a potential treatment for AML.

In subsequent tests on mouse models of AML, investigators learned that if they delivered the drug in small doses over an extended period of time, it would eventually force the problematic immature stem cells to die off without harming normal cells.

“You can block DHODH, but if you block it too well, then every cell dies. If you block it just enough, the normal cells will survive, but the leukemia cells mature and die,” Sykes explained.

It's not clear why leukemia cells are more susceptible to the reduction in uridine than normal cells, and answering that question could be the next big challenge in Syke's research career.

“But the exciting part for AML patients is that Brequinar has been in humans already, and we are working hard to get that molecule or another inhibitor of the DHODH enzyme back into humans as fast as possible,” Sykes said.

As of February 2017, there are four pharmaceutical companies with highly potent DHODH inhibitors (similar to Brequinar) already in their clinical pipeline, Sykes said. It is expected that the first Phase 1 clinical trials in AML patients will begin in early 2018.

“It’s kind of crazy when you realize that we’ve all come at this target from a different direction, but clearly DHODH has been on some people’s minds for some time.”

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