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Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells
Kazuhito Naka1,2, Kaori Ishihara1, Yoshie Jomen1
1Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Abstract:
Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW-7197 to CML-affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW-7197 plus TKI was effective in eliminating CML-LICs even if they expressed the TKI-resistant T315I mutant BCR-ABL1 oncogene. Collectively, these results indicate that EW-7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML-LICs.
Insights
EW-7197 combined with tyrosine kinase inhibitors (TKIs) effectively targets chronic myeloid leukemia stem cells, including resistant types. This combination therapy shows promise for delaying relapse and improving survival in CML patients.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Current chronic myeloid leukemia (CML) treatment strategies focus on tyrosine kinase inhibitors (TKIs).
- Eradicating CML leukemia-initiating cells (CML-LICs) remains a challenge for TKI therapy.
- The therapeutic benefits of targeting CML-LICs are not fully understood.
Purpose of the Study:
- To investigate the therapeutic potential of EW-7197, a transforming growth factor-β signaling inhibitor, against CML-LICs.
- To evaluate the efficacy of combining EW-7197 with TKIs in a preclinical CML model.
Main Methods:
- EW-7197, an orally bioavailable TGF-β signaling inhibitor, was administered to CML-affected mice.
- Combination therapy involved TKI plus EW-7197.
- Therapeutic effects were assessed by monitoring disease relapse and survival rates.
Main Results:
- Combined TKI and EW-7197 treatment significantly delayed disease relapse and prolonged survival compared to TKI alone.
- The combination therapy effectively eliminated CML-LICs, including those with the TKI-resistant T315I mutant BCR-ABL1 oncogene.
- EW-7197 demonstrated in vivo efficacy in suppressing CML-LICs.
Conclusions:
- EW-7197 shows promise as a novel therapeutic agent for CML.
- Combining EW-7197 with TKIs may overcome TKI resistance and eradicate CML-LICs.
- This combination strategy could offer significant benefits for CML patients.
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