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Down‐regulation of the Notch pathway mediated by a γ‐secretase inhibitor induces anti‐tumour effects in mouse models of T‐cell leukaemia
Author(s) -
Tammam J,
Ware C,
Efferson C,
O'Neil J,
Rao S,
Qu X,
Gorenstein J,
Angagaw M,
Kim H,
Kenific C,
Kunii K,
Leach KJ,
Nikov G,
Zhao J,
Dai X,
Hardwick J,
Scott M,
Winter C,
Bristow L,
Elbi C,
Reilly JF,
Look T,
Draetta G,
Van der Ploeg LHT,
Kohl NE,
Strack PR,
Majumder PK
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00389.x
Subject(s) - notch signaling pathway , gamma secretase , apoptosis , cancer research , pharmacology , in vivo , biology , signal transduction , microbiology and biotechnology , biochemistry
Background and purpose: γ‐Secretase inhibitors (GSIs) block NOTCH receptor cleavage and pathway activation and have been under clinical evaluation for the treatment of malignancies such as T‐cell acute lymphoblastic leukaemia (T‐ALL). The ability of GSIs to decrease T‐ALL cell viability in vitro is a slow process requiring > 8 days, however, such treatment durations are not well tolerated in vivo . Here we study GSI's effect on tumour and normal cellular processes to optimize dosing regimens for anti‐tumour efficacy. Experimental approach: Inhibition of the Notch pathway in mouse intestinal epithelium was used to evaluate the effect of GSIs and guide the design of dosing regimens for xenograft models. Serum Aβ 40 and Notch target gene modulation in tumours were used to evaluate the degree and duration of target inhibition. Pharmacokinetic and pharmacodynamic correlations with biochemical, immunohistochemical and profiling data were used to demonstrate GSI mechanism of action in xenograft tumours. Key results: Three days of >70% Notch pathway inhibition was sufficient to provide an anti‐tumour effect and was well tolerated. GSI‐induced conversion of mouse epithelial cells to a secretory lineage was time‐ and dose‐dependent. Anti‐tumour efficacy was associated with cell cycle arrest and apoptosis that was in part due to Notch‐dependent regulation of mitochondrial homeostasis. Conclusions and implications: Intermittent but potent inhibition of Notch signalling is sufficient for anti‐tumour efficacy in these T‐ALL models. These findings provide support for the use of GSI in Notch‐dependent malignancies and that clinical benefits may be derived from transient but potent inhibition of Notch.