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Updated: Jun 11, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting DLL4 in tumors shows preclinical activity but potentially significant toxicity
Ji-Liang Li1, Adrian M Jubb, Adrian L Harris
1Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. ji-liang.li@imm.ox.ac.uk
Abstract:
Evaluation of: Yan M, Callahan CA, Beyer JC et al.: Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6-E7 (2010). Delta-like ligand 4 (DLL4) is a Notch ligand that is critical in the formation of a functional vascular network in tumors. Blockade of DLL4-mediated Notch signaling strikingly increases nonproductive angiogenesis, but significantly inhibits tumor growth in preclinical mouse models. Thus, DLL4 has emerged as an attractive target for cancer therapy. Anti-DLL4 antibodies have recently entered clinical trials. However, the potential toxic effects of anti-DLL4 are poorly understood. In this article, Yan et al. reported that chronic DLL4 blockade abnormally activates endothelial cells, causes pathological changes of multiple organs and induces vascular neoplasms. The findings need confirmation in further studies using different tumor-bearing animals but, nevertheless, raise important safety concerns regarding the use of anti-DLL4 agents and warrant monitoring for these effects in clinical trials for targeting DLL4.
Insights
Chronic blockade of Delta-like ligand 4 (DLL4) in cancer therapy may cause vascular neoplasms and organ damage. Further studies are needed to confirm these findings and monitor safety in clinical trials.
Area of Science:
- Oncology
- Vascular Biology
- Drug Development
Background:
- Delta-like ligand 4 (DLL4) is a crucial Notch ligand for tumor vascular network formation.
- DLL4 blockade enhances anti-tumor effects by increasing nonproductive angiogenesis and inhibiting tumor growth in preclinical models.
- Anti-DLL4 antibodies are being investigated as cancer therapeutics and have entered clinical trials.
Discussion:
- Yan et al. report that chronic DLL4 blockade leads to abnormal endothelial cell activation.
- This blockade was observed to cause pathological changes in multiple organs and induce vascular neoplasms in preclinical studies.
- These findings highlight potential toxicities associated with DLL4-targeted therapies.
Key Insights:
- Chronic DLL4 blockade can induce vascular neoplasms.
- Endothelial cell activation and multi-organ pathological changes are potential adverse effects.
- DLL4 is a promising cancer target, but its blockade requires careful safety evaluation.
Outlook:
- Further studies are required to validate these findings in diverse tumor models.
- Clinical trials targeting DLL4 should closely monitor for vascular neoplasms and organ toxicity.
- Understanding and mitigating these risks is crucial for the safe clinical application of anti-DLL4 agents.
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