CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model
✍ Scribed by 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
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- French
- Weight
- 527 KB
- Volume
- 129
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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.