An NCI-designated Comprehensive Cancer Center
By Katie Neith | March 7, 2018
Zhang-Amber-Bin Bin Zhang, M.D., Ph.D.
City of Hope scientists and doctors may have discovered a more effective treatment for patients with chronic myelogenous leukemia (CML) using a drug that was developed at the institution to eradicate CML stem cells, according to a study published today in Nature Medicine.

CML is a type of cancer that starts in the blood-forming cells of the bone marrow and invades the blood. Although there are first-line drug treatments, called tyrosine kinase inhibitors (TKIs), to induce long-term remission in CML patients, leukemia stem cells, which initiate and maintain the disease, frequently persist and can result in a relapse of the disease. TKIs are also expensive and a patient with CML needs to take the drug for life.

City of Hope researchers aimed to find a treatment for CML that was effective enough for people to stop using TKIs. In their quest to find a cure for the disease, the team tested a drug called miristen. Developed at City of Hope, miristen targets one type of a microRNA that is expressed in leukemia stem cells, known as miR-126, which researchers believe to be important for self-renewal and persistence of stubborn leukemia stem cells.

Led by Bin Zhang, M.D., Ph.D., an associate research professor in City of Hope's Department of Hematologic Malignancies Translational Science, and Guido Marcucci, M.D., chair and professor of the Department of Hematologic Malignancies Translational Science, and director, Gehr Family Center for Leukemia Research, the team tested various combinations of miristen and other drugs in mouse models with CML. These included miristen with TKIs and without them.

The best results were seen in those treated with miristen and a TKI. Transplantation of the bone marrow cells collected from those treated with miristen and TKIs resulted in no sign of leukemia in the healthy recipient mice, meaning all leukemia stem cells were eliminated. The researchers believe that miristen simply makes the TKIs more effective in killing the leukemia stem cells.

This is could be a major breakthrough for people who are in remission for CML because there is always a concern that the disease will come back if TKI treatment is stopped,” Zhang said. “Miristen could be the drug that sends the disease into permanent remission.”
Guido Marcucci Guido Marcucci, M.D.
Zhang and Marcucci noted that their research also unearthed another important finding for CML that was key to the treatment’s success. The team discovered that endothelial cells in the blood vessels of a person’s bone marrow — where CML begins — contain high levels of miR-126. These endothelial cells transfer miR-126 to leukemia stem cells, essentially feeding the cancer what it needs to survive and relapse. The researchers hypothesized that to eliminate CML, miristen had to lower miR-126 in both the leukemia stem cells and the endothelial cells. Testing of their idea showed that it does.

“What we have discovered is how the microenvironment surrounding the leukemia stem cells supports them and how you need to target miR-126 in the leukemia stem cells and the microenvironment to completely eradicate the disease,” Marcucci said. “Our current study showed these findings may also apply to other types of leukemia.”

City of Hope is currently working on bringing miristen from the laboratory to the clinic for treatment in patients.

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