Research at the MU School of Medicine has found a potentially exciting new use for an old drug.
In September, Dr. Xunlei Kang received a $1.7 million grant to study a novel treatment for acute myeloid leukemia, or AML.
Kang’s research aims to repurpose a type of medication used to manage the levels of blood sugar and A1C in Type 2 diabetes patients. The treatment inhibits an enzyme called dipeptidyl peptidase-4, or DPP-4.
He and his research assistant, Chen Wang, are testing these inhibitors as a way to treat acute myeloid leukemia, which affects nearly 20,000 new patients each year, according to the American Cancer Society.
“Over the past 30 to 40 years, AML is the only blood cancer with no progress in treatment,” Wang said.
Acute myeloid leukemia is a bone marrow cancer that disrupts the creation of myeloid stem cells.
Healthy myeloid stem cells will develop into red blood cells, platelets or white blood cells. In a patient with acute myeloid leukemia, however, the body creates abnormal leukemia cells called blasts.
These blasts build up in the body, leaving progressively less room for healthy cells. Without the proper number of blood cells, patients with this type of leukemia can experience anemia, bleed easily and have a severely compromised immune system.
A core difficulty in treating this type of leukemia is its sporadic nature, since the patient’s body still produces some healthy stem cells. But with chemotherapy, even healthy cells are destroyed, leaving the patient compromised and vulnerable to infection.
“If you want to delete an AML cell, you will also delete the normal human cells,” Kang said. “That can be intolerable for patients, so we needed to identify the specific targets.”
This prompted him to study the effect of DPP-4 inhibitors on immunodeficient mice. A group of these mice were treated with DPP-4 inhibitors to see if their survival rate improved, compared to a group that received no treatment.
The results have been promising so far, Kang said. DPP-4 inhibitors have not seemed to affect their lifespan or ability to reproduce, and the mice treated with the inhibitors are living 20% to 30% longer.
Kang said he was drawn to this research because of the severity of the disease and the absence of effective new treatments.
“With AML patients, the average survival time is around two years. The five-year survival rate is 28%,” he said. “It’s a challenging disease to treat.”
The common form of treatment for most acute myeloid leukemia patients under age 65 is a chemotherapy called Seven Plus Three, a reference to the number days in a row each of its two chemicals are taken.
The treatment is incredibly tough on patients because it destroys many of the body’s healthy cells.
As a hematologist and oncologist, Dr. Donald Doll regularly treats such patients, either through chemotherapy or experimental drugs in clinical trials.
Doll is assisting Kang’s research by providing blood samples from his leukemia patients. Right now Kang is only testing the effects of DPP-4 on the AML cells that naturally develop in mice, but the next step in the research will involve human samples.
The term for it is patient derived xenograft model, or PDX. Researchers inject immunodeficient mice with human AML cells, giving them the human variant of the disease.
Once that is done, Kang can test the DPP-4 inhibitors on a human version of acute myeloid leukemia.
Provided that the mouse doesn’t reject the human cells, these rodents can be used to study the effects of treatment without putting humans at risk.
Doll is currently treating a patient with acute myeloid leukemia who could benefit from Kang’s research results.
The patient started treatment after complaining of weakness and fatigue, Doll said. He was found to have a high white count, low hemoglobin and low platelets.
“When he came, he pretty much felt fine. We had to tell him: You have acute leukemia, and we want to give you chemotherapy. You’re probably going to be here for about a month, “ Doll explained.
Most patients do feel fine for a week after chemotherapy, but they begin to experience side effects eight days or more after the treatment.
“You start getting sick because we’ve wiped out all the blood cells by giving them the chemo,” Doll said. “Now they don’t have any white blood cells, any red blood cells or any platelets.”
Typically, a patient spends a week in chemotherapy and is then given supportive care, antibiotics and blood products. When they return three weeks after treatment, their blood counts have usually recovered.
There is a chance, however, that the cancer does not go into remission, in which case the cancer returns a second time and is even harder to treat due to the patient’s compromised state from the chemo.
“That recent patient I treated, he didn’t go into remission,” Doll said. “So he’s sicker now than when he came in here. Sometimes patients get better and leave, but some may not respond to chemotherapy.”
Often those patients will be directed toward clinical trials of new treatment types.
“In my opinion, you should try a clinical trial for AML if you have access to one,” Doll said. “A lot of people require stem cell transplants, so we are always looking for something better.”