Biological Roles of the Delta Family Notch Ligand Dll4 in Tumor and Endothelial Cells in Ovarian Cancer

Abstract

Emerging evidence suggests that the Notch/Delta-like ligand 4 (DLL4) pathway may offer important new targets for anti-angiogenesis approaches. In this study, we investigated the clinical and biological significance of DLL4 in ovarian cancer. DLL4 was overexpressed in 72% of tumors examined where it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of DLL4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased DLL4 expression in the tumor vasculature. Immobilized DLL4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of DLL4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining DLL4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared to control or treatment with bevacizumab alone. Together, our findings establish that DLL4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer, and that targeting DLL4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.

A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors

“…Notch is a key pathway in ovarian cancer, and Dll4 is overexpressed in up to 72% of ovarian carcinomas (15,29). Enoticumab had activity in patients with ovarian cancer, not only serous papillary type (PR), but also in endometrioid and transitional cell tumors (SD > 6 months).…”

“…Increased Dll4 expression has been noted in several tumor types (4,(13)(14)(15), and it may be associated with worse outcomes (13,(15)(16)(17). Preclinically, Dll4 blockade has activity against tumor xenografts such as colorectal, sarcoma, lung, breast, pancreas cancers, melanoma, and glioma, and includes tumors resistant to anti-VEGF agents (7,11,18).…”

Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer

“…In human tumors, Dll4 expression is typically restricted to the tumor vasculature, and low to undetectable in the vasculature of adjacent normal tissue (13,(18)(19)(20)(21)(22). In breast and ovarian cancer, Dll4 expression appears correlated to clinical outcome (18,23).…”

New Strategies in the Treatment of Ovarian Cancer: Current Clinical Perspectives and Future Potential

“…Preclinical studies have shown that silencing of EZH2 using siRNA inhibits angiogenesis and ovarian cancer growth (15). Dll4 has been associated with poor outcome following anti-VEGF therapy and RNA interferencemediated silencing of Dll4 has been shown to reduce angiogenesis and tumor growth in ovarian cancer models (16). This approach appears promising and a phase I clinical trial of REGN 421, a monoclonal antibody against Dll4, is underway.…”