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

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.

• 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
• Journal: Leukemia (Leukemia) Vol. 28 Issue 2 Pg. 278-88 (Feb 2014) ISSN: 1476-5551 [Electronic] England
• PMID: 23774673 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Receptor, Notch1
• Dexamethasone

Topics

• Adolescent
• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Child
• Child, Preschool
• Dexamethasone (administration & dosage, pharmacology)
• Disease Models, Animal
• Drug Synergism
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Mice
• Molecular Targeted Therapy
• Neoplasm Staging
• Neoplastic Stem Cells (drug effects, metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Receptor, Notch1 (antagonists & inhibitors, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays