ctce-9908 and Disease-Models--Animal

The majority of prostate cancer (Pca) patient morbidity can be attributed to bone metastatic events, which poses a significant clinical obstacle. Therefore, a better understanding of this phenomenon is imperative and might help to develop novel therapeutic strategies. Stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4 have been implicated as regulators of bone resorption and bone metastatic development, suggesting that agents able to suppress this signaling pathway may be used as pharmacological treatments. In this study we studied if two CXCR4 receptor antagonists, Plerixafor and CTE9908, may affect bone metastatic disease induced by Pca in preclinical experimental models. To verify the hypothesis that CXCR4 inhibition affects Pca metastatic disease, selective CXCR4 compounds, Plerixafor, and CTE9908, were tested in preclinical models known to generate bone lesions. Additionally, the expression levels of CXCR4 and SDF-1α were analyzed in a number of human tissues derived from primary tumors, lymph-nodes and osseous metastases of Pca as well as in a wide panel of human Pca cell lines to non-tumorigenic and tumorigenic phenotype.. Bone-derived Pca cells express higher CXCR4 levels than other Pca cell lines. This differential expression was also observed in human Pca samples. In vitro evidence supports the hypothesis that factors produced by bone microenvironment differentially sustain CXCR4 and SDF1-α expression with respect to prostate microenvironment determining increased efficacy toward Plerixafor. The use of SDF1-α neutralizing antibodies greatly reduced the increase of CXCR4 expression in cells co-cultured with bone stromal cells (BMSc) and to a lesser extent in cells co-cultured with prostate stromal cells (HPSc) and partially reduced SDF1-α Plerixafor efficacy. SDF-1α induced tumor cell migration and invasion, as well as MMP-9, MMP-2, and uPA expression, which were reduced by Plerixafor. The incidence of X-ray detectable bone lesions was significantly reduced following Plerixafor and CTE9908 treatment Kaplan-Meier probability plots showed a significant improvement in the overall survival of mice treated with Plerixafor and CTE9908. The reduced intra-osseous growth of PC3 and PCb2 tumor cells after intratibial injection, as a result of Plerixafor and CTE9908 treatment, correlated with decreased osteolysis and serum levels of both mTRAP and type I collagen fragments (CTX), which were significantly lower with respect to controls.. Our report provides novel information on the potential activity of CXCR4 inhibitors on the formation and progression of Pca bone and soft tissue metastases and supports a biological rationale for the use of these inhibitors in men at high risk to develop clinically evident bone lesions.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Benzylamines; Blotting, Western; Bone Neoplasms; Cell Adhesion; Cell Movement; Chemokine CXCL12; Coculture Techniques; Cyclams; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Heterocyclic Compounds; Heterografts; Humans; Immunohistochemistry; Lymph Nodes; Lymphatic Metastasis; Male; Mice; Mice, Nude; Peptides; Prostatic Neoplasms; Receptors, CXCR4; Tomography, X-Ray Computed; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

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

CXCL12/CXCR4 signaling may be involved in tumor growth and angiogenesis, and homing of cancer cells to bone and other organs. Our purpose was to determine whether inhibition of CXCR4 with a peptide-based antagonist would reduce tumor growth and metastasis of breast cancer.. We used two mouse models of breast cancer. In the first model, 1 x 10(6) MDA-MB-231 breast cancer cells transfected with luciferase were implanted into the inguinal mammary fat pad to produce primary tumors. In the second model, 1 x 10(5) MDA-231-BSC12 cells were injected into the left cardiac ventricle to produce bone metastases. CTCE-9908, a peptide analog of CXCL12 that competitively binds to CXCR4, was used to test the effect of inhibiting CXCR4. Five mice from each mouse model were treated with CTCE-9908 (25 mg/kg, injected subcutaneously 5 d/wk). All mice were assessed weekly using bioluminescent imaging to quantify relative volumes of tumor burden.. Bioluminescencent imaging showed that the mice treated with CTCE-9908 had significantly less primary tumor burden than the control mice. At 5 and 6 wk, the mice treated with CTCE-9908 had a 7-fold reduction and 5-fold reduction in primary tumor burden, respectively. Treatment with CTCE-9908 also significantly inhibited the rate of metastases compared with the control group. At 5 and 6 wk, the mice treated with CTCE-9908 demonstrated a 9-fold reduction and 20-fold reduction in metastatic tumor burden, respectively.. Treatment with the CXCR4 antagonist CTCE-9908 significantly reduced metastasis as well as primary tumor growth in mouse models of breast cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Mice; Mice, Nude; Peptides; Receptors, CXCR4; Treatment Outcome; Xenograft Model Antitumor Assays