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23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity
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| Zeitschriftentitel: | Molecular Cancer Therapeutics |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , |
| In: | Molecular Cancer Therapeutics, 14, 2015, 8, S. 1858-1867 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
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| Schlagwörter: |
| author_facet |
Proia, Theresa Jiang, Feng Bell, Alisa Nicoletti, Richard Kong, Lingxin Kreuter, Kelly Poling, Laura Winston, William M. Flaherty, Meghan Weiler, Solly Perino, Samantha O'Hagan, Ronan Lin, Jie Gyuris, Jeno Okamura, Heidi Proia, Theresa Jiang, Feng Bell, Alisa Nicoletti, Richard Kong, Lingxin Kreuter, Kelly Poling, Laura Winston, William M. Flaherty, Meghan Weiler, Solly Perino, Samantha O'Hagan, Ronan Lin, Jie Gyuris, Jeno Okamura, Heidi |
|---|---|
| author |
Proia, Theresa Jiang, Feng Bell, Alisa Nicoletti, Richard Kong, Lingxin Kreuter, Kelly Poling, Laura Winston, William M. Flaherty, Meghan Weiler, Solly Perino, Samantha O'Hagan, Ronan Lin, Jie Gyuris, Jeno Okamura, Heidi |
| spellingShingle |
Proia, Theresa Jiang, Feng Bell, Alisa Nicoletti, Richard Kong, Lingxin Kreuter, Kelly Poling, Laura Winston, William M. Flaherty, Meghan Weiler, Solly Perino, Samantha O'Hagan, Ronan Lin, Jie Gyuris, Jeno Okamura, Heidi Molecular Cancer Therapeutics 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity Cancer Research Oncology |
| author_sort |
proia, theresa |
| spelling |
Proia, Theresa Jiang, Feng Bell, Alisa Nicoletti, Richard Kong, Lingxin Kreuter, Kelly Poling, Laura Winston, William M. Flaherty, Meghan Weiler, Solly Perino, Samantha O'Hagan, Ronan Lin, Jie Gyuris, Jeno Okamura, Heidi 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-14-1104 <jats:title>Abstract</jats:title> <jats:p>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. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.</jats:p> 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity Molecular Cancer Therapeutics |
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| title |
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_unstemmed |
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_full |
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_fullStr |
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_full_unstemmed |
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_short |
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_sort |
23814, an inhibitory antibody of ligand-mediated notch1 activation, modulates angiogenesis and inhibits tumor growth without gastrointestinal toxicity |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1535-7163.mct-14-1104 |
| publishDate |
2015 |
| physical |
1858-1867 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>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. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.</jats:p> |
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| author | Proia, Theresa, Jiang, Feng, Bell, Alisa, Nicoletti, Richard, Kong, Lingxin, Kreuter, Kelly, Poling, Laura, Winston, William M., Flaherty, Meghan, Weiler, Solly, Perino, Samantha, O'Hagan, Ronan, Lin, Jie, Gyuris, Jeno, Okamura, Heidi |
| author_facet | Proia, Theresa, Jiang, Feng, Bell, Alisa, Nicoletti, Richard, Kong, Lingxin, Kreuter, Kelly, Poling, Laura, Winston, William M., Flaherty, Meghan, Weiler, Solly, Perino, Samantha, O'Hagan, Ronan, Lin, Jie, Gyuris, Jeno, Okamura, Heidi, Proia, Theresa, Jiang, Feng, Bell, Alisa, Nicoletti, Richard, Kong, Lingxin, Kreuter, Kelly, Poling, Laura, Winston, William M., Flaherty, Meghan, Weiler, Solly, Perino, Samantha, O'Hagan, Ronan, Lin, Jie, Gyuris, Jeno, Okamura, Heidi |
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| description | <jats:title>Abstract</jats:title> <jats:p>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. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.</jats:p> |
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| spelling | Proia, Theresa Jiang, Feng Bell, Alisa Nicoletti, Richard Kong, Lingxin Kreuter, Kelly Poling, Laura Winston, William M. Flaherty, Meghan Weiler, Solly Perino, Samantha O'Hagan, Ronan Lin, Jie Gyuris, Jeno Okamura, Heidi 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-14-1104 <jats:title>Abstract</jats:title> <jats:p>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. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.</jats:p> 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity Molecular Cancer Therapeutics |
| spellingShingle | Proia, Theresa, Jiang, Feng, Bell, Alisa, Nicoletti, Richard, Kong, Lingxin, Kreuter, Kelly, Poling, Laura, Winston, William M., Flaherty, Meghan, Weiler, Solly, Perino, Samantha, O'Hagan, Ronan, Lin, Jie, Gyuris, Jeno, Okamura, Heidi, Molecular Cancer Therapeutics, 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity, Cancer Research, Oncology |
| title | 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_full | 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_fullStr | 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_full_unstemmed | 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_short | 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| title_sort | 23814, an inhibitory antibody of ligand-mediated notch1 activation, modulates angiogenesis and inhibits tumor growth without gastrointestinal toxicity |
| title_unstemmed | 23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1535-7163.mct-14-1104 |