دورية أكاديمية
أعرض في EDS

Inhibition of Notch4 Using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium.

التفاصيل البيبلوغرافية
العنوان: Inhibition of Notch4 Using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium.
المؤلفون: Eng JW; Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, Illinois.; Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, Illinois., Kato Y; Eisai Co., Ltd, Tsukuba, Japan., Adachi Y; Eisai Co., Ltd, Tsukuba, Japan., Swaminathan B; Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, Illinois., Naiche LA; Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, Illinois., Vadakath R; Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, Illinois., Sakamoto Y; KAN Research Institute, Inc., Kobe, Japan., Nakazawa Y; Eisai Co., Ltd, Tsukuba, Japan., Tachino S; Eisai Co., Ltd, Tsukuba, Japan., Ito K; Eisai Co., Ltd, Tsukuba, Japan., Abe T; Eisai Co., Ltd, Tsukuba, Japan., Minoshima Y; Eisai Co., Ltd, Tsukuba, Japan., Hoshino-Negishi K; KAN Research Institute, Inc., Kobe, Japan., Ogasawara H; KAN Research Institute, Inc., Kobe, Japan., Kawakatsu T; KAN Research Institute, Inc., Kobe, Japan., Nishimura M; KAN Research Institute, Inc., Kobe, Japan., Katayama M; Eisai Co., Ltd, Tsukuba, Japan., Shimizu M; Eisai Co., Ltd, Tsukuba, Japan., Tahara K; Eisai Co., Ltd, Tsukuba, Japan., Sato T; Eisai Co., Ltd, Tsukuba, Japan., Suzuki K; Eisai Co., Ltd, Tsukuba, Japan., Agarwala K; Eisai Co., Ltd, Tsukuba, Japan., Iwata M; Eisai Co., Ltd, Tsukuba, Japan., Nomoto K; Eisai Inc., Woodcliff, New Jersey., Ozawa Y; Eisai Co., Ltd, Tsukuba, Japan., Imai T; KAN Research Institute, Inc., Kobe, Japan., Funahashi Y; Eisai Co., Ltd, Tsukuba, Japan., Matsui J; Eisai Inc., Woodcliff, New Jersey., Kitajewski J; Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, Illinois.; University of Illinois Cancer Center, Chicago, Illinois.
المصدر: Cancer research communications [Cancer Res Commun] 2024 Jul 01; Vol. 4 (7), pp. 1881-1893.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: Print Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Philadelphia, Pennsylvania] : American Association for Cancer Research, [2021]-
مواضيع طبية MeSH: Receptor, Notch4*/metabolism , Neovascularization, Pathologic*/drug therapy , Neovascularization, Pathologic*/pathology , Neovascularization, Pathologic*/metabolism , Antibodies, Neutralizing*/pharmacology , Antibodies, Neutralizing*/therapeutic use, Animals ; Mice ; Humans ; Female ; Cell Line, Tumor ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; Disease Models, Animal ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Cell Proliferation/drug effects ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Breast Neoplasms/metabolism
مستخلص: Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms.
Significance: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.
(©2024 The Authors; Published by the American Association for Cancer Research.)
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معلومات مُعتمدة: R01 HL112626 United States HL NHLBI NIH HHS; UL1 TR002003 United States TR NCATS NIH HHS
المشرفين على المادة: 0 (Receptor, Notch4)
0 (Antibodies, Neutralizing)
0 (NOTCH4 protein, human)
146991-60-8 (Notch4 protein, mouse)
تواريخ الأحداث: Date Created: 20240710 Date Completed: 20240731 Latest Revision: 20240802
رمز التحديث: 20240802
مُعرف محوري في PubMed: PMC11289863
DOI: 10.1158/2767-9764.CRC-24-0081
PMID: 38984877
قاعدة البيانات: MEDLINE
الوصف
تدمد:2767-9764
DOI:10.1158/2767-9764.CRC-24-0081