How to Stop Leukemia from Returning? Block β-catenin Pathway

Focusing on the β-catenin pathway
Dr. Armstrong and his colleagues focused on the so-called β-catenin pathway — a pathway known to be important in blood stem cells during their early development but not in adulthood.

What the researchers found in their study on mice was that leukemia stem cells revert back to their dependence on this β-catenin pathway, leaving them vulnerable to treatments aimed at this pathway.

As expected, when the researchers gave β-catenin inhibitors to the mice, this helped eliminate leukemia stem cells — as did a pain-relieving drug already in use that lowers β-catenin levels indirectly. What this suggests is that combining imatinib with β-catenin inhibitors can help to prevent the recurrence of the blood cancer.

Even better, the β-catenin blockers got rid of leukemia and its stem cells once and for all in lab mice, but left the healthy blood stem cells unscathed.

“The appeal is that this pathway is important for the leukemia, but not for normal cells,” Dr. Armstrong says. “It gives us an angle for therapy.”

But more work has to be done to ensure that β-catenin blockers work just as well in people as they do in mice, Dr. Armstrong cautions. And if these blockers do, CML patients aren’t the only ones who will benefit from the new treatment strategy — these blockers may also be used for harder-to-treat forms of cancer, and to treat patients who have entered the acute stage of CML or those who suffer from colon cancer.

Other authors also associated with the Harvard Stem Cell Institute Cancer Program and the Dana-Farber Harvard Cancer Center as well as the Children’s Hospital in Boston, and two German cancer institutes — one at the University Hospital of Otto-von-Guericke University and another at the University Hospital Ulm, as well as the Queensland Institute for Medical Research in Australia are Dr. Florian H. Heidel, Dr. Lars Bullinger, Dr. Zhaohui Feng, Dr. Zhu Wang, Dr. Tobias A. Neff, Dr. Lauren Stein, Dr. Demetrios Kalaitzidis and Dr. Steven W. Lane.

London researchers come to the same conclusion
But Dr. Armstrong’s team wasn’t the first to identify the role of the β-catenin pathway in the progression and drug-resistance of leukemia stem cells. The credit goes to a team of British scientists at the King’s College London led by Dr. Eric So. This team was the first to identify the role the β-catenin proteins play in the blood cancer — but in a more aggressive form caused by mutations of the MLL gene.

Writing on December 13, 2010 in the journal Cancer Cell, Dr. So’s team also concluded that leukemic stem cells can be reversed to a pre-leukemic stage by suppressing the β-catenins. The King’s College researchers also found that advanced leukemic stem cells that had become resistant to treatment could be “re-sensitized” to treatment by suppressing the same protein. They had also been doing early work on lab mice.

Even better, the British scientists were investigating leukemic stem cells found in the more aggressive form of leukemia — which accounts for 70 percent of infant leukemias and one in ten of adult leukemias. In infants, the prognosis for this type of leukemia isn’t good — only half survive past two years after receiving standard anti-leukemia treatment.

The gravity and aggressiveness of this form of leukemia only highlights the significance of the findings from Dr. So’s team.

“Most of the current anti-cancer therapies used to treat leukemia attack healthy blood cells as well as cancerous ones,” Dr. So notes. “Interestingly, β-catenin is not required for normal blood stem cells. So if we can specifically target β-catenin in the bone marrow, we can have potentially a more effective and less toxic anti-leukemia therapy that can efficiently eradicate leukemic stem cells but spare healthy blood stem cells,” he said — and his thoughts are echoed more recently by Harvard’s Dr. Armstrong.

“Much more research needs to be done before we can adopt this approach in treating people with leukemia, but the findings of this study do look promising,” he said.

The King’s college researchers have since gone on to investigate the mechanisms behind these molecular changes in a bid to find out why β-catenin is so important in the development of MLL leukemia.