Targeting Notch Signaling with a Notch2/Notch3 Antagonist (Tarextumab) Inhibits Tumor Growth and Decreases Tumor-Initiating Cell Frequency

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 21(9); 2084–95. ©2015 AACR.

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

“…In addition, effects on Notch signaling were revealed by the downregulation of genes such as NOTCH1 and PSEN1. Both Wnt and Notch pathways are associated with CSCs (43)(44)(45). Consistently, numerous stem cell genes were inhibited by anti-RSPO3 in the three responders.…”

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…The Notch activity involves in the process of differentiation, proliferation, and apoptotic programs in all stages of development of the organisms. There is evidence that aberrant activation of the Notch signalling pathway plays a crucial role in the process of ovarian carcinogenesis and chemoresistance in ovarian cancer patients 26, 27. A previous GWAS‐based pathway analysis found that NCOR2 , NCSTN and MAML2 variants in the Notch signalling pathway predicted survival in patients with cutaneous melanoma 20.…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…Preclinical data show antitumor, antiangiogenesis effects and decreasing CSCs frequency following treatment with these receptor-specific antibodies (93)(94)(95). Based on the success of Notch-specific antibodies, OMP-52M51 (antiNotch1) and OMP-59R5 (anti-Notch2/3) have been studied in clinical trials.…”