Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.
Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.
When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.
Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.
Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.
The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.
Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.
The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.
To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.
In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.
In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.
The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.
In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.
The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.
Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.
In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.
These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.
“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”
