AsianScientist (Apr. 18, 2013) – Researchers from the RIKEN Center for Integrative Medical Sciences in Japan have identified a new compound that could someday prevent relapse in acute myeloid leukemia patients.
In a study published in Science Translational Medicine, they show that this compound reduces the risk of relapse in a mouse model of the human disease.
Acute myeloid leukemia (AML) is an acute type of blood cancer that starts in the blood-forming cells in the bone marrow. AML is the most common type of acute leukemia in adults. While many patients are able to fight off the disease at first with conventional chemotherapy, long-term outcomes in the majority of patients are poor due to disease relapse.
“To improve patient outcomes, it is crucial to understand the mechanisms of AML relapse and to develop effective treatment strategies to reduce AML relapse,” said Dr. Ishikawa, who led the study.
Over the last decade, bone marrow cells called leukemia stem cells (LSC) have been recognized as key players in human AML pathogenesis as well as chemotherapy resistance and relapse. Previous studies have suggested that LSCs might cause relapse if they are not properly eliminated by conventional chemotherapy.
By transplanting LSCs obtained from AML patient samples into immune-deficient newborn mice, Ishikawa and his team developed a mouse model for AML, which they used to study AML and LSCs.
Using this model, they were able to identify a protein (HCK) present in higher quantities in human AML LSCs than in normal blood-forming stem cells, and that could be used as a target for therapeutic agents against human AML LSCs.
In the present study, the researchers screened a library of tens of thousands of small molecules and isolated a HCK inhibitor that was highly active against patient-derived AML LSCs grown in culture. In their AML mouse model, the molecule resulted in a significant reduction of human AML cells in the blood, as well as a reduction of human AML LSCs in the bone marrow of the mice.
In particular, in mice engrafted with human AML derived from patients with the FLT3-ITD mutation, one of the mutations associated with worse clinical outcomes, the administration of the small molecule led to nearly complete elimination of both AML LSCs and non-stem AML cells in the bone marrow of multiple bones (femur, tibia, sternum, and spine) as well as the spleen and peripheral blood.
The researchers are hopeful that this treatment may be used in AML patients, but more work needs to be done, they said.
“We now plan to proceed with a more in-depth biochemical and pharmacologic characterization of this compound in the lab, to find out whether it is safe and to determine which subset of AML patients could benefit from it. Ultimately, we hope to develop a drug that can be used in the clinic, Ishikawa said.
The article can be found at: Saito Y et al. (2013) A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo.
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Source: RIKEN; Photo: pennstatenews/Flickr/CC.
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