Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia.
OBJECTIVE
gamma-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.


METHODS
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 Abeta(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.


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
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.
Tammam
J
J
Department of Oncology/Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
Ware
C
C
Efferson
C
C
O'Neil
J
J
Rao
S
S
Qu
X
X
Gorenstein
J
J
Angagaw
M
M
Kim
H
H
Kenific
C
C
Kunii
K
K
Leach
K J
KJ
Nikov
G
G
Zhao
J
J
Dai
X
X
Hardwick
J
J
Scott
M
M
Winter
C
C
Bristow
L
L
Elbi
C
C
Reilly
J F
JF
Look
T
T
Draetta
G
G
Van der Ploeg
Lht
L
Kohl
N E
NE
Strack
P R
PR
Majumder
P K
PK
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003106:Colon / Q000166:cytology / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015536:Down-Regulation; D004334:Drug Administration Schedule; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000097:blood; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013830:Thiadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D003499:Cyclic S-Oxides; C523799:MRK 003; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D051881:Receptor, Notch1; D013830:Thiadiazoles; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases