CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model.

Abstract

CXCR4 is a chemokine receptor implicated in the homing of cancer cells to target metastatic organs, which overexpress its ligand, stromal cell-derived factor (SDF)-1. To determine the efficacy of targeting CXCR4 on primary tumor growth and metastasis, we used a peptide inhibitor of CXCR4, CTCE-9908, that was administered in a clinically relevant approach using a transgenic breast cancer mouse model. We first performed a dosing experiment of CTCE-9908 in the PyMT mouse model, testing 25, 50 and 100 mg/kg versus the scrambled peptide in groups of 8-16 mice. We then combined CTCE-9908 with docetaxel or DC101 (an anti-VEGFR2 monoclonal antibody). We found that increasing doses of CTCE-9908 alone slowed the rate of tumor growth, with a 45% inhibition of primary tumor growth at 3.5 weeks of treatment with 50 mg/kg of CTCE-9908 (p = 0.005). Expression levels of VEGF were also found to be reduced by 42% with CTCE-9908 (p = 0.01). In combination with docetaxel, CTCE-9908 administration decreased tumor volume by 38% (p = 0.02), an effect that was greater than that observed with docetaxel alone. In combination with DC101, CTCE-9908 also demonstrated an enhanced effect compared to DC101 alone, with a 37% decrease in primary tumor volume (p = 0.01) and a 75% reduction in distant metastasis (p = 0.009). In combination with docetaxel or an anti-angiogenic agent, the anti-tumor and anti-metastatic effects of CTCE-9908 were markedly enhanced, suggesting potentially new effective combinatorial therapeutic strategies in the treatment of breast cancer, which include targeting the SDF-1/CXCR4 ligand/receptor pair.

• Authors: Saima Hassan, Marguerite Buchanan, Kaushar Jahan, Adriana Aguilar-Mahecha, Louis Gaboury, William J Muller, Yaqoob Alsawafi, Anna A Mourskaia, Peter M Siegel, Ombretta Salvucci, Mark Basik
• Journal: International journal of cancer (Int J Cancer) Vol. 129 Issue 1 Pg. 225-32 (Jul 01 2011) ISSN: 1097-0215 [Electronic] United States
• PMID: 20830712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 UICC.

Chemical References

• Antineoplastic Agents
• CTCE-9908
• Peptides
• Receptors, CXCR4
• Taxoids
• Vascular Endothelial Growth Factor A
• Docetaxel

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Division (drug effects)
• Disease Models, Animal
• Docetaxel
• Immunohistochemistry
• Male
• Mammary Neoplasms, Experimental (pathology)
• Mice
• Mice, Transgenic
• Neoplasm Metastasis (prevention & control)
• Peptides (pharmacology)
• Receptors, CXCR4 (antagonists & inhibitors)
• Taxoids (pharmacology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)