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Targeting the Notch1 and mTOR pathways in a mouse T-ALL model
Kathleen Cullion1, Kyle M Draheim, Nicole Hermance
1Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Blood
|February 28, 2009
Summary
Gamma-secretase inhibitors (GSIs) show promise in treating T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting NOTCH1 signaling and inducing cancer cell death. Combination therapy with rapamycin enhances these anti-leukemic effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- NOTCH1 mutations are common in T-cell acute lymphoblastic leukemia (T-ALL).
- Gamma-secretase inhibitors (GSIs) induce T-ALL cell growth arrest and apoptosis in vitro.
- GSIs are being investigated as potential T-ALL therapeutics.
Purpose of the Study:
- To evaluate the in vivo antileukemic activity of GSIs in T-ALL.
- To investigate the combined efficacy of GSIs and rapamycin in T-ALL treatment.
Main Methods:
- Treatment of leukemic mice with a GSI (MRK-003).
- Assessment of Notch1 target gene expression and apoptosis in vivo.
- Combination therapy with GSIs and rapamycin in T-ALL cell lines and a mouse xenograft model.
Main Results:
- GSI treatment significantly extended survival in leukemic mice.
- NOTCH1 inhibition in vivo repressed target gene expression and increased apoptosis.
- Combined GSI and rapamycin treatment ablated mTOR kinase activity, induced apoptosis, and inhibited human T-ALL growth in xenografts.
Conclusions:
- Targeting NOTCH1 with GSIs is a viable therapeutic strategy for T-ALL.
- Inhibiting both NOTCH1 and mTOR pathways offers enhanced efficacy for T-ALL treatment.
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