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

• DOI: 10.1038/leu.2013.183
• Publication Date: 2013-06-18T06:37:15Z
• Authors: V Agnusdei; S Minuzzo; C Frasson; A Grassi; F Axelrod; S Satyal; A Gurney; T Hoey; E Seganfreddo; G Basso; S Valtorta; R M Moresco; A Amadori; S Indraccolo
• Keywords: 0301 basic medicine; Adolescent; Antineoplastic Agents; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Dexamethasone; predictive biomarkers; Mice; 03 medical and health sciences; Animals; Humans; Molecular Targeted Therapy; Receptor, Notch1; Child; Neoplasm Staging; Notch1; Gene Expression Regulation, Leukemic; apoptosis; Notch1; predictive biomarkers; T-ALL; apoptosis; Antibodies, Monoclonal; Drug Synergism; targeted therapy; Xenograft Model Antitumor Assays; Tumor Burden; 3. Good health; Disease Models, Animal; Child, Preschool; Neoplastic Stem Cells; T-ALL; Notch1; T-ALL; apoptosis; targeted therapy; predictive biomarkers

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.