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DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency

Timothy Hoey1, Wan-Ching Yen, Fumiko Axelrod

  • 1OncoMed Pharmaceuticals Inc., Redwood City, CA 94063, USA. timothy.hoey@oncomed.com

Cell Stem Cell
|August 12, 2009
PubMed

Insights

Targeting DLL4 signaling with specific antibodies inhibits tumor growth and reduces cancer stem cells. Combining anti-human and anti-mouse DLL4 antibodies proved more effective than monotherapy for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • DLL4 signaling is crucial for angiogenesis and tumor growth.
  • Previous research indicates blocking DLL4 can impede tumor progression.

Purpose of the Study:

  • To develop and evaluate selective anti-DLL4 antibodies for targeting tumor and host vasculature.
  • To elucidate the mechanisms by which DLL4 inhibition affects tumor growth, proliferation, and cancer stem cells.

Main Methods:

  • Development of selective anti-human and anti-mouse DLL4 antibodies.
  • Utilizing human tumor xenograft models in mice.
  • Analysis of Notch target gene expression, cell proliferation, and cancer stem cell frequency via flow cytometry and in vivo tumorigenicity assays.

Main Results:

  • Both anti-human and anti-mouse DLL4 antibodies demonstrated tumor growth inhibition.
  • Combination therapy with both antibodies yielded superior efficacy compared to single-agent treatment.
  • Inhibition of human DLL4 reduced Notch target gene expression and tumor cell proliferation.
  • Targeting human DLL4, alone or with irinotecan, decreased cancer stem cell frequency.

Conclusions:

  • Selective DLL4 inhibition is a viable strategy for reducing tumor growth and cancer stem cells.
  • Combination targeting of DLL4 in both tumor and host offers enhanced therapeutic potential.
  • DLL4 blockade impacts tumor cell proliferation and stemness, suggesting a role in overcoming treatment resistance.

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