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For the past few decades, people diagnosed with almost any type of malignant blood cancer followed a similar treatment plan. It worked for some types of leukemia, but there was a high rate of relapse and many patients had only limited chances for long-term survival. Scientists simply hadn’t learned enough about what causes rare blood diseases, much less how to interrupt the process that helps bad cells grow.
Today, a relatively new technology in the hands of scientists like Reuben Kapur, PhD, is unraveling mysteries that could resolve the knowledge gap and make it possible to thwart many forms of blood cancer. Kapur, a professor at the Indiana University School of Medicine, leads the Hematologic Malignancies and Stem Cell Biology Research Group at the Herman B Wells Center for Pediatric Research.
Finding new drugs that can defeat acute myeloid leukemia (AML) is one of the group’s top priorities. As a well-known site for treatment of kids with complex conditions, Riley at IU Health and its clinicians work closely with researchers at the Wells Center to improve treatment for malignancies such as AML, a rare blood cancer with an average survival rate of only five years.
“Unlike some forms of pediatric blood cancers, AML is still a nasty disease to treat,” says Kapur. “Through Riley at IU Health, we are blessed not only to have clinicians who are very good, but access to patients who have many types of hematologic malignancies, including AML, T-cell acute lymphoblastic leukemia (TALL) and bone marrow failure syndromes such as fanconi anemia.”
Leukemia occurs in the same stem cells that produce normal cells in a healthy body. Kapur has devoted much of his life to learning why some people acquire changes in their stem cells and others don’t. “When a mutation occurs, normal stem cells become leukemic and these bad cells can take over and grow like crazy,” he says.
Helping kids has been a big source of inspiration for Kapur’s work. “It can be devastating to learn that a child as young as one, two or three years of age has only a 50 percent probability of living a full life,” he says. “I’ve been very privileged to combine research on adult and pediatric blood cancers, but finding a novel cure for a pediatric population that has an entire lifetime ahead of them will probably be more impactful.”
At the Wells Center, progress often starts with basic science experiments using mice, which are 96 percent similar to humans in terms of their genetic traits. “We first test everything in mouse models,” Kapur says. “Then, if there is some efficacy, we draw cells from patients and see, in a laboratory pre-clinical setting, how the patient-derived cells respond to the drugs we’ve created—whether they respond the way mouse cells do or whether there are any differences.”
If the reaction is favorable, scientists create a mouse xenograft model, which injects human-derived leukemic cells into mice. These preclinical trials allow researchers to see how the disease progresses and determine which drugs interfere with pathways that go awry in patients with various forms of blood cancer.
A combination of computer science, physics, chemistry, math, engineering and biology drives the innovation underway in Kapur’s research group. Access to genome sequencing technology allows scientists like Kapur to pinpoint genes altered by blood cancer by comparing the DNA sequences of normal and leukemic patients.
Using cloning techniques, they can cut pieces of DNA drawn from patients with leukemia and introduce them to normal cells in a laboratory setting to see whether they produce leukemia. “Once those genes are identified, we can learn how mutation in the gene contributes to leukemia,” he says.
After researchers identify the pathways perturbed by leukemia, they begin what may be the most challenging stage of all. “That’s when the chemists on campus and elsewhere come into play, helping us devise strategies to block the various pathways that get revved up in these leukemic cells,” Kapur says.
In the best circumstances, the process leads to Phase I clinical trials, where patients who do not respond to FDA-approved drugs can become part of the research. “As a group, we’ve been able to identify some new drugs for AML that are in preclinical trials, and we hope that we can develop them enough to take them to Phase I and Phase II clinical trials for the pediatric population.”
Their work is part of the next big wave in healthcare—personalized medicine. “Rather than treating patients based on what their leukemia is telling us, we are changing our approach and treating patients based on what their DNA is telling us.”