Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency

The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling. We utiliz...

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Bibliographic Details
Published in:Clinical cancer research 2015-05, Vol.21 (9), p.2084-2095
Main Authors: Yen, Wan-Ching, Fischer, Marcus M, Axelrod, Fumiko, Bond, Christopher, Cain, Jennifer, Cancilla, Belinda, Henner, William R, Meisner, Rene, Sato, Aaron, Shah, Jalpa, Tang, Tracy, Wallace, Breanna, Wang, Min, Zhang, Chun, Kapoun, Ann M, Lewicki, John, Gurney, Austin, Hoey, Timothy
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
Antineoplastic Agents - pharmacology
Humans
Immunohistochemistry
Mice
Neoplasms, Experimental - drug therapy
Neoplastic Stem Cells - drug effects
Oligonucleotide Array Sequence Analysis
Real-Time Polymerase Chain Reaction
Receptor, Notch2 - antagonists & inhibitors
Receptor, Notch3
Receptors, Notch - antagonists & inhibitors
Xenograft Model Antitumor Assays
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Summary:The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling. We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature. These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-14-2808