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Ref Type Journal Article
PMID (23774673)
Authors Agnusdei V, Minuzzo S, Frasson C, Grassi A, Axelrod F, Satyal S, Gurney A, Hoey T, Seganfreddo E, Basso G, Valtorta S, Moresco RM, Amadori A, Indraccolo S
Title Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts.
Journal Leukemia
Vol 28
Issue 2
Date 2014 Feb
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Brontictuzumab Brontictuzumab 8 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
Brontictuzumab OMP-52M51 NOTCH1 Antibody 2 Brontictuzumab (OMP-52M51) is a monoclonal antibody that binds Notch1 and prevents ligand interaction and pathway activation, which may inhibit angiogenesis and tumor growth (PMID: 23774673, PMID: 31616059, PMID: 29726923).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 act mut acute lymphoblastic leukemia sensitive Brontictuzumab Preclinical - Pdx Actionable In a preclinical study, xenograft models of patient-derived acute lymphocytic leukemia cells harboring NOTCH1 activating muatations demonstrated better response to Brontictuzumab (OMP-52M51) compared to NOTCH1 wild-type models (PMID: 23774673). 23774673