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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|