Abstract
Inhibition of NOTCH1 signaling with γ-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.
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Acknowledgements
Supported by the NIH (grants R01CA120196 and R01CA129382), the Leukemia and Lymphoma Society (grants 1287-08 and 6237-08) (AF) and Fondo de Investigacion Sanitaria (grant CD07/00033) (PJR). Adolfo Ferrando is a Leukemia and Lymphoma Society Scholar.
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Real, P., Ferrando, A. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23, 1374–1377 (2009). https://doi.org/10.1038/leu.2009.75
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DOI: https://doi.org/10.1038/leu.2009.75