ctce-9908 and Neoplasm-Metastasis

Can biochip arrays identify which individuals with metastatic disease will respond to an anti-metastatic agent?. Cytokine and cell adhesion arrays (Randox Ltd) were measured over 1 month in 9 research participants receiving CTCE-9908 in a Phase I/II study.. Research participants with stable disease (n=2) had significantly higher soluble VCAM-1 as compared to those that progressed.. VCAM-1 measurement early during CTCE-9908 treatment might be used as a surrogate for response.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Cell Adhesion Molecules; Cytokines; Demography; Drug Screening Assays, Antitumor; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Peptides; Protein Array Analysis

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.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Division; Disease Models, Animal; Docetaxel; Immunohistochemistry; Male; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Neoplasm Metastasis; Peptides; Receptors, CXCR4; Taxoids; Vascular Endothelial Growth Factor A