ctce-9908 and Prostatic-Neoplasms

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

CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface is thought to mediate tumor growth and subsequent development of metastatic disease. CTCE-9908 is a known inhibitor of CXCR4. Herein, we tested the efficacy of CTCE-9908 in inhibiting prostate cancer cell growth, invasion, and metastasis.. We used a panel of in vitro assays utilizing human prostate cancer cell lines and an in vivo orthotopic prostate cancer model to assess the anti-tumoral activity of CTCE-9908.. We demonstrated that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 and C4-2B cells; (b) 50 μg/ml of CTCE-9908 inhibited the invasive properties of PC-3 cells; (c) 25 mg/kg of CTCE-9908 did not alter primary tumor growth but it did significantly reduce total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues. Histological analysis showed that CTCE-9908 treatment resulted in tumor necrosis in primary prostate tumors and no significant change in proliferation of tumor cells as measured by Ki-67 staining; (d) CTCE-9908 inhibited the tumor angiogenesis as measured by CD34 positive vessels in tumors.. These data suggest that CXCR4 inhibition by CTCE-9908 decreases the invasion potential in vitro, which then translated to a reduction of tumor spread with associated reduction in angiogenesis. Hence, CTCE-9908 may prove to be an efficacious novel agent to prevent and treat the spread of metastatic prostate cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Humans; Male; Molecular Targeted Therapy; Peptides; Prostatic Neoplasms; Receptors, CXCR4; Treatment Outcome

Recent reports have linked the survival-promoting effect of CXCR4 to the up regulation of Bcl-2 protein expression.. To further elucidate the relationship between Bcl-2 and CXCR4, tumorigenicity was evaluated in in vitro and in vivo models following treatment with CTCE-9908, a CXCR4 antagonist peptide.. In vitro, CTCE-9908 inhibited cellular proliferation in PC-3-Bcl-2 and PC-3-Neo cell lines Furthermore in our xenograft model, CTCE-9908 delivered via daily intraperitoneal injections resulted in a statistically significant reduction in tumor size compared to control (396 + 205 mm(3) vs. 1,010 + 215 mm(3) respectively, p < 0.05) in the Bcl-2 expressing tumors. This reduction was associated with knockdown of VEGF, inhibition of angiogenesis and lymphangiogenesis, and induction of apoptosis. CTCE-9908 therapy was also associated with a marked reduction in intra-tumoral host cells expressing VEGFR1 and CD11b myeloid-derived suppressor cells (MDSC).. These data show that CXCR4 antagonists represent a valuable addition to the cancer therapeutic arsenal. Such agents may have beneficial synergistic dual-effects in reducing tumor cell proliferation directly, and indirectly through perturbation of the tumor microenvironment. Further studies of the novel CTCE-9908 compound in prostate and other solid tumor inhibition are warranted. Prostate 69: 1460-1469, 2009. (c) 2009 Wiley-Liss, Inc.

Topics: Animals; Antineoplastic Agents; CD11b Antigen; Cell Division; Cell Line, Tumor; Down-Regulation; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Peptides; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptors, CXCR4; Vascular Endothelial Growth Factor Receptor-1; Xenograft Model Antitumor Assays