NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia

PJ Real, AA Ferrando - Leukemia, 2009 - nature.com
PJ Real, AA Ferrando
Leukemia, 2009nature.com
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 …
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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