Anti-DLL4 has broad spectrum activity in pancreatic cancer dependent on targeting DLL4-notch signaling in both tumor and vasculature cells

Wan Ching Yen, Marcus M. Fischer, Mark Hynes, Jingjiang Wu, Edward Kim, Lucia Beviglia, V. Pete Yeung, Xiaomei Song, Ann M. Kapoun, John Lewicki, Austin Gurney, Diane M. Simeone, Timothy Hoey

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Purpose: We previously showed that targeting Delta-like ligand 4 (DLL4) in colon and breast tumors inhibited tumor growth and reduced tumor initiating cell frequency. In this report, we have extended these studies to pancreatic cancer and probed the mechanism of action in tumor and stromal cells involved in antitumor efficacy. Experimental Design: Patient-derived pancreatic xenograft tumor models were used to evaluate the antitumor effect of anti-DLL4. To investigate the mechanism of action, we compared the activity of targeting DLL4 in tumor cells with an anti-human DLL4 antibody (anti-hDLL4) and in the host stroma/vasculature with an anti-mouse DLL4 antibody (anti-mDLL4). The effect of these antibodies on cancer stem cell frequency was examined by in vivo limiting dilution assays. Results: The combination of anti-hDLL4 and anti-mDLL4 was efficacious in a broad spectrum of pancreatic tumor xenografts and showed additive antitumor activity together with gemcitabine. Treatment with either anti-hDLL4 or anti-mDLL4 delayed pancreatic tumor recurrence following termination of gemcitabine treatment, and the two together produced an additive effect. Anti-hDLL4 had a pronounced effect in reducing the tumorigenicity of pancreatic cancer cells based on serial transplantation and tumor-sphere assays. In contrast, disruption of tumor angiogenesis with anti-mDLL4 alone or with anti-VEGF had minimal effects on tumorigenicity. Gene expression analyses indicated that anti-DLL4 treatment regulated genes that participate in Notch signaling, pancreatic differentiation, and epithelial-to-mesenchymal transition. Conclusions: Our findings suggest a novel therapeutic approach for pancreatic cancer treatment through antagonism of DLL4/Notch signaling.

Original languageEnglish (US)
Pages (from-to)5374-5386
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number19
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Anti-DLL4 has broad spectrum activity in pancreatic cancer dependent on targeting DLL4-notch signaling in both tumor and vasculature cells'. Together they form a unique fingerprint.

Cite this