title: 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.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Agnusdei
authors.affiliation: Dipartimento Scienze Chirurgiche, Oncologiche e Gastroenterologiche -Sez. Oncologia e Immunologia, Università di Padova, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Minuzzo
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, Università di Padova, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Frasson
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Grassi
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Axelrod
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Satyal
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gurney
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hoey
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, Università di Padova, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Seganfreddo
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, Università di Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: Nuclear Medicine Department, San Raffaele Scientific Institute; Fondazione Tecnomed, University of Milan Bicocca; IBFM-CNR, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Valtorta
authors.affiliation: Nuclear Medicine Department, San Raffaele Scientific Institute; Fondazione Tecnomed, University of Milan Bicocca; IBFM-CNR, Milan, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Moresco
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Amadori
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D000293:Adolescent; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051881:Receptor, Notch1; D003907:Dexamethasone