Abstract
Researchers identified a small molecule that stimulates the production of stem cells in umbilical cord blood, potentially expanding treatment options for adults with hematologic cancers.
Researchers have identified a small molecule that stimulates the production of hematopoietic stem cells (HSC) in umbilical cord blood, improving the likelihood of successful transplants for many adults with blood-related cancers.
In the recently published study, researchers identified a prototype molecule, dubbed UM171, that when introduced into an automated fed–batch culture system promotes robust expansion of human cord blood stem cells (Science 2014;345:1509–12). Cord blood is the preferred source of stem cells when a transplant candidate cannot be matched with a family donor, because its naïve T cells are less likely to induce graft-versus-host disease. However, such transplants have been limited mostly to children because a single umbilical cord typically contains too few stem cells to treat an adult.
Guy Sauvageau, PhD, a hematologist at Maisonneuve-Rosemont Hospital's Hematopoietic Stem Cell Transplantation Program, which is affiliated with the University of Montreal in Canada, and his team screened a library of more than 5,000 low–molecular weight compounds for their ability to expand peripheral blood cells enriched with long-term HSCs (LT-HSC) and zeroed in on UM729. They then examined more than 300 newly synthesized analogues of UM729 and found that one—UM171—was 10 to 20 times more potent in stimulating the expansion of HSC-enriched cells.
The researchers hypothesize that UM171 works by enhancing the action of LT-HSCs, which show a delayed engraftment pattern and the capability to repopulate and produce mature blood cells indefinitely, thus lowering the risk of graft failure. UM171 promotes LT-HSC self-renewal independently of aryl hydrocarbon receptor suppression, which has also been shown to promote cord blood cell expansion but appears to produce mainly nonrenewing, short-lived progenitor cells.
“If the new process works, an expanded cord-blood transplant could become the best option when a patient doesn't have a family-matched donor,” says Jean Roy, MD, a hematologist working with Sauvageau who will lead the upcoming clinical trials for UM171. Such a development would particularly affect nonwhite transplant candidates, who often have no therapeutic options due to a lack of compatible donors.
Roy aims to begin a phase I clinical trial this month that will include patients with hematologic malignancies who require an urgent transplant or cannot be matched with an unrelated registry donor. Researchers plan to enroll 15 patients at Canadian transplant facilities in Montreal, Quebec City, and Vancouver.
The trial is expected to conclude by December 2015, says Roy. If the results are positive, researchers will launch a larger, 50-patient phase II study.
“At the present time, only about 5% of all adult allogeneic transplants are using cord blood because of low stem-cell count,” says Roy. “This study represents a scientific breakthrough that could lead to a clinical breakthrough with wide applicability to patients.”
Researchers have found a way to stimulate the production of hematopoietic stem cells in cord blood (left). When introduced to the prototype molecule UM171, the cells proliferate and remain in their undifferentiated state (right).
Researchers have found a way to stimulate the production of hematopoietic stem cells in cord blood (left). When introduced to the prototype molecule UM171, the cells proliferate and remain in their undifferentiated state (right).
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