Clinical management of pancreatic cancer is challenging and in recent years has not been dramatically improved and this disease remains the fourth most common cause of cancer-related death. Dysregulated Notch2 and/or Notch3 activity has been associated with several human tumor types including pancreatic cancer. In this report, we describe the development of OMP-59R5, an antibody isolated originally by binding to Notch2 and subsequently found to also bind Notch3. OMP-59R5 potently blocks Notch2 and Notch3 signaling and inhibits the growth pancreatic cancer patient derived xenograft tumors, as a single agent and in combination with gemcitabine. The anti-tumor effects were associated with modulation of Notch target genes in tumor and stromal cells. Inclusion of OMP-59R5 delayed pancreatic tumor recurrence following termination of gemcitabine, correlated with an effect of anti-Notch2/3 in decreasing in cancer stem cell frequency and tumorigenicity. Gene set enrichment analysis showed that a subset of the stem cell gene sets and gene set related to epithelial-to-mesenchymal transistion, EMT, was up-regulated in tumors by gemcitabine alone, but down-regulated by the combination of gemcitabine plus OMP-59R5 treatment. Findings from the present study suggest that agents that reduce cancer cell frequency may improve cancer treatment by delaying or preventing tumor recurrence, and reducing the metastatic spread of the disease. In particular, blocking Notch-mediated proliferation of bulk tumor cells and cancer stem cells may provide an attractive strategy for novel therapy in pancreatic cancer treatment.
Citation Format: Wan-Ching Yen, Marcus Fischer, Aaron Sato, Min Wang, Ann M. Kapoun, John Lewicki, Austin Gurney, Timothy Hoey. Targeting Notch signaling with a dual Notch 2/3 antagonist, OMP-59R5, inhibits tumor growth and decreases cancer stem cell frequency in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B44.