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Leukemia. 2014 Feb;28(2):278-88. doi: 10.1038/leu.2013.183. Epub 2013 Jun 18.

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts.

Author information

1
UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
2
Dipartimento Scienze Chirurgiche, Oncologiche e Gastroenterologiche -Sez. Oncologia e Immunologia, Università di Padova, Padova, Italy.
3
Oncohematology Laboratory, Department of Woman and Child Health, Università di Padova, Padova, Italy.
4
OncoMed Pharmaceuticals Inc., Redwood City, CA, USA.
5
Nuclear Medicine Department, San Raffaele Scientific Institute; Fondazione Tecnomed, University of Milan Bicocca; IBFM-CNR, Milan, Italy.
6
1] UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, Italy [2] Dipartimento Scienze Chirurgiche, Oncologiche e Gastroenterologiche -Sez. Oncologia e Immunologia, Università di Padova, Padova, Italy.

Abstract

T-acute lymphoblastic leukemia (T-ALL) is characterized by several genetic alterations and poor prognosis in about 20-25% of patients. Notably, about 60% of T-ALL shows increased Notch1 activity, due to activating NOTCH1 mutations or alterations in the FBW7 gene, which confer to the cell a strong growth advantage. Therapeutic targeting of Notch signaling could be clinically relevant, especially for chemotherapy refractory patients. This study investigated the therapeutic efficacy of a novel anti-Notch1 monoclonal antibody by taking advantage of a collection of pediatric T-ALL engrafted systemically in NOD/SCID mice and genetically characterized with respect to NOTCH1/FBW7 mutations. Anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing Notch1 mutations, including samples derived from poor responders or relapsed patients. Notably, the therapeutic efficacy of anti-Notch1 therapy was significantly enhanced in combination with dexamethasone. Anti-Notch1 treatment increased T-ALL cell apoptosis, decreased proliferation and caused strong inhibitory effects on Notch-target genes expression along with complex modulations of gene expression profiles involving cell metabolism. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia-initiating cell functions. These results show therapeutic efficacy of Notch1 blockade for T-ALL, highlight the potential of combination with dexamethasone and identify surrogate biomarkers of the therapeutic response.

PMID:
23774673
DOI:
10.1038/leu.2013.183
[Indexed for MEDLINE]

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