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Efficacy of NAMPT inhibition in T-cell acute lymphoblastic leukemia
Chelsea Vrana1, Matthew Zhang1, Max Rochette1
1Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Abstract:
Novel agents targeting upregulated signaling pathways are needed to improve outcomes in T-cell acute lymphoblastic leukemia (T-ALL), since conventional cytotoxic chemotherapy regimens have reached the limits of tolerability. We identified upregulated, targetable signaling pathways common to both human T-ALL samples and a KrasLSL-G12D/+.Mb1Cre/+ murine model of T-ALL. We found the NAMPT inhibitor FK866 had the greatest cytotoxicity of a panel of small molecule inhibitors tested in human and mouse T-ALL cell lines, and in patient derived xenograft (PDX)-expanded T-ALL patient samples. We subsequently tested FK866 in vivo in PDX mouse models of T-ALL, and found that it significantly reduced the peripheral blood disease burden and prolonged the survival of leukemic mice (median survival of 60.5 vs 21 days, p = 0.0007). This screen for targetable pathways in T-ALL generated in vitro and in vivo preclinical data supporting NAMPT inhibition as a promising strategy for the treatment of T-ALL.
Insights
Novel research shows that inhibiting the NAMPT pathway with FK866 is a promising new treatment for T-cell acute lymphoblastic leukemia (T-ALL). This approach significantly reduced leukemia in mice, offering hope beyond traditional chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Conventional chemotherapy for T-cell acute lymphoblastic leukemia (T-ALL) has limitations in tolerability and efficacy.
- There is a critical need for novel therapeutic agents targeting specific signaling pathways in T-ALL.
Purpose of the Study:
- To identify and validate targetable signaling pathways in T-ALL.
- To evaluate the efficacy of NAMPT inhibition as a therapeutic strategy for T-ALL.
Main Methods:
- Screening of small molecule inhibitors against human and murine T-ALL cell lines and patient-derived xenografts (PDX).
- In vitro cytotoxicity assays and in vivo studies using PDX mouse models of T-ALL.
- Identification of upregulated signaling pathways common to human T-ALL and a Kras-driven murine T-ALL model.
Main Results:
- The NAMPT inhibitor FK866 demonstrated the highest cytotoxicity among tested agents in T-ALL models.
- FK866 treatment significantly reduced peripheral blood disease burden in T-ALL bearing mice.
- FK866 administration substantially prolonged survival in leukemic mice (median survival 60.5 vs 21 days).
Conclusions:
- NAMPT inhibition represents a promising therapeutic strategy for T-cell acute lymphoblastic leukemia.
- Preclinical data support FK866 as a potential novel agent for T-ALL treatment.
- Targeting upregulated pathways offers a new avenue for T-ALL therapy beyond conventional chemotherapy.
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