NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia.
Inhibition of NOTCH1 signaling with gamma-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.
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
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D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000517:prevention & control; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011499:Protein Processing, Post-Translational; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000072056:Transcription Factor HES-1
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C078493:HES1 protein, human