Thursday, 18 April 2013

Researchers identify compound that could prevent acute myeloid leukemia relapses

In a new study on mice, researchers from the RIKEN Institute, Japan have discovered a compound that could be used to prevent cancer relapse in acute myeloid leukaemia (AML) patients, especially the ones carrying the FLT3-ITD mutation.

AML is a relatively rare blood cancer that starts from the hematopoietic stem cells (HSCs) of the bone marrow. AML accounts for approximately 1.2% of cancer deaths in the U.S. and is the second most common form of leukaemia in children. Typically, the first line of defence against AML consists of chemotherapy, which at first yields quite good results. However, long-term outcomes tend to be very poor due to 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,” explains Dr. Ishikawa, leading author of the study.

The main reason behind the high relapse ratio is that current treatments, like chemotherapy, are not effective against cancer stem cells, the main culprit behind AML.

In previous studies, the same research team had found that a protein called hematopoietic cell kinase (HCK) is present in higher amounts in human leukemia stem cells (LSCs) than it is in HSCs, and had the potential to be used as a molecular target for therapeutic agents.

In this study, the researchers first extracted LSCs from AML patients and then transplanted them into newly born mice. This way, they developed a mouse model to study both AML and LSCs. Then, they performed a large-scale chemical library screen of small molecules that might act as therapeutic agents by inhibiting HCK which led them to a small molecule, called RK-20449, that was highly active against patient-derived LSCs grown in culture.

To confirm its efficiency, they administered this molecule to the AML mice and found that it greatly reduced the numbers of all AML-related cells including the LSCs in the bone marrow.

Furthermore, they found that the molecule was particularly effective in the mice that carried LSCs from patients with the FLT3-ITD mutation, a mutation associated with the worst clinical prognosis. Specifically, the molecule almost wiped out all AML cells, including the LSCs.

The study concludes by stating that RK-20449 "may help reduce relapse in AML patients”.

Although the findings are very optimistic, the researchers say that more research is still needed to assess the drug's safety and efficacy before moving to human applications.

Educational video about acute myeloid leukaemia


Reference
Saito, Y., Yuki, H., Kuratani, M., Hashizume, Y., Takagi, S., Honma, T., Tanaka, A., Shirouzu, M., Mikuni, J., Handa, N., Ogahara, I., Sone, A., Najima, Y., Tomabechi, Y., Wakiyama, M., Uchida, N., Tomizawa-Murasawa, M., Kaneko, A., Tanaka, S., Suzuki, N., Kajita, H., Aoki, Y., Ohara, O., Shultz, L., Fukami, T., Goto, T., Taniguchi, S., Yokoyama, S., & Ishikawa, F. (2013). A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo Science Translational Medicine, 5 (181), 181-181 DOI: 10.1126/scitranslmed.3004387

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