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Ref Type Journal Article
PMID (25995436)
Authors Proia T, Jiang F, Bell A, Nicoletti R, Kong L, Kreuter K, Poling L, Winston WM, Flaherty M, Weiler S, Perino S, O'Hagan R, Lin J, Gyuris J, Okamura H
Title 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity.
Journal Molecular cancer therapeutics
Vol 14
Issue 8
Date 2015 Aug
URL
Abstract Text Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit.

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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
23814 23814 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
23814 NOTCH1 Antibody 2 23814 is a monoclonal antibody that binds to the Notch1 ligand-binding domain and inhibits ligand-mediated signaling, potentially resulting in decreased tumor growth (PMID: 25995436).
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
Unknown unknown fibrosarcoma not applicable Tivozanib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with Tivozanib (AV-951) resulted in partial inhibition of tumor growth and decreased tumor vasulature in a fibrosarcoma cell line xenograft model (PMID: 25995436). 25995436
Unknown unknown fibrosarcoma not applicable 23814 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with 23814 resulted in partial inhibition of tumor growth in a fibrosarcoma cell line xenograft model (PMID: 25995436). 25995436
ERBB2 V659E breast cancer sensitive 23814 + Tivozanib Preclinical Actionable In a preclinical study, the combination of 23814 and Tivozanib (AV-951) inhibited tumor growth in several transgenic mouse models of breast cancer expressing ERBB2 (HER2) V659E, including those with resistance to VEGFR inhibitors (PMID: 25995436). 25995436
Unknown unknown renal cell carcinoma not applicable 23814 Preclinical - Pdx Actionable In a preclinical study, treatment with 23814 resulted in tumor growth inhibition in a renal cell carcinoma patient-derived xenograft (PDX) model (PMID: 25995436). 25995436
Unknown unknown fibrosarcoma not applicable 23814 + Tivozanib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of 23814 and Tivozanib (AV-951) resulted in tumor growth inhibition in a fibrosarcoma cell line xenograft model, with increased efficacy over either agent alone (PMID: 25995436). 25995436