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