Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer.

Abstract

CXCL12/CXCR4 signaling, being important in the homing of cancer cells to lungs, bone and other organs, is a promising therapeutic target. Our purpose was to determine whether a peptide-based antagonist of CXCR4 would reduce primary tumor growth and/or metastasis in a preclinical mouse model of inflammatory breast cancer. We improved an existing model of inflammatory breast cancer for this study by luciferase transfection of SUM149 cells and the monitoring of such cells in mice by imaging and the luciferase assay. We implanted 2 x 10(6) SUM49-Luc cells along with matrigel into the left thoracic mammary fat pad of nude mice to produce tumors. Our mouse model exhibited important features of inflammatory breast cancer, namely, aggressive local disease, local metastases and distant metastases. To evaluate the efficacy of a CXCR4 antagonist CTCE-9908, by itself or in combination with paclitaxel, we treated groups of ten mice each with CTCE-9908 (25 mg/kg, injected subcutaneously 5 days/week), control peptide SC-9908, paclitaxel (10 mg/kg, injected subcutaneously twice a week), and CTCE-9908 plus paclitaxel concurrently. We assessed all mice weekly by whole-body luciferase imaging to quantify relative primary tumor burden and distant metastases. At the end of the experiment, we quantified primary tumors by weight and lung metastases by luciferase activity assay on tissue lysates. Paclitaxel, a known chemotherapeutic, inhibited primary tumor growth in our model (P < 0.05). CTCE-9908 did not significantly inhibit primary tumor growth or lung metastases as compared to control groups, without or with paclitaxel (P > 0.05). However, CTCE-9908 as a single therapy inhibited organ-specific metastasis to leg (P < 0.05 by chi-squared test and by two-sample t-test).

• Authors: Balraj Singh, Kendra R Cook, Cecilia Martin, Eugene H Huang, Kailash Mosalpuria, Savitri Krishnamurthy, Massimo Cristofanilli, Anthony Lucci
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 27 Issue 4 Pg. 233-40 (Apr 2010) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 20229045 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CTCE-9908
• CXCR4 protein, human
• Peptides
• Receptors, CXCR4
• Paclitaxel

Topics

• Animals
• Breast Neoplasms (drug therapy, immunology, pathology)
• Cell Line, Tumor
• Female
• Humans
• Inflammation (drug therapy)
• Lung Neoplasms (drug therapy, immunology, secondary)
• Mice
• Mice, Nude
• Paclitaxel (pharmacology, therapeutic use)
• Peptides (administration & dosage, pharmacology, therapeutic use)
• Receptors, CXCR4 (antagonists & inhibitors, biosynthesis, immunology)
• Xenograft Model Antitumor Assays