Photo by Aaron Logan
Lab mice
Targeting two pathways simultaneously—one critical for oncogenesis and one essential for cell survival—may be an effective strategy for treating acute myeloid leukemia (AML), according to researchers.
The team studied mouse models of FLT3-ITD AML and found an inhibitor targeting the FLT3 pathway was largely effective against the disease.
However, targeting the BCL-2 pathway as well proved even more effective, completely eliminating AML in most cases.
Fumihiko Ishikawa, MD, PhD, of RIKEN Center for Integrative Medical Sciences in Yokohama, Kanagawa, Japan, and his colleagues described this work in Science Translational Medicine.
The researchers noted that mutations observed in AML patients have also been observed in elderly people without AML. So the team set out to determine which mutations actually contribute to the disease.
The researchers obtained bone marrow or blood samples from patients with FLT3-ITD AML and transplanted different cellular populations from each individual into mice. The team then examined how the cells behaved.
They were surprised to find that cells with similar surface marker profiles behaved differently. Therefore, the team used single-cell genomic sequencing to correlate mutational profiles with malignant potential.
The researchers said their results suggest that FLT3-ITD is “a critical trigger for leukemia initiation,” and it cooperates with accumulated mutations in DNMT3A, TET2, NPM1, and/or WT1.
The team went on to treat the FLT3-ITD AML mice with RK-20449, a FLT3/HCK inhibitor, and they observed “significant responses.”
In fact, RK-20449 eradicated leukemia originating from 5 different patients. The recipient mice experienced complete elimination of AML cells, in spite of the fact that they also carried mutations not directly targeted by RK-20449.
However, the researchers also noted the presence of RK-20449-resistant AML cells in some mice. The team therefore theorized that co-inhibition of an antiapoptotic signal—BCL-2—might remedy this.
So they treated resistant mice with the BCL-2 inhibitor venetoclax as well as RK-20449. The combination produced responses in all mice treated and completely eliminated AML cells in 9 of 12 cases.
“This shows that determining which of the mutations in a diverse landscape are critical in leukemia onset and which of the pathways are critical for therapeutic resistance in leukemia, and simultaneously targeting those pathways, is an encouraging way to treat difficult cancers such as AML,” Dr Ishikawa said.
