Abstract 716: CXCR4 antagonist, CTCE-9908, inhibits PC-3 cell invasiveness and metastasis

Chemokines and their receptors function in the migration and homing of cells to target tissues. Current evidence suggests that cancer cells activate chemokines and their receptors during dissemination and metastasis formation at secondary sites. Previously, in prostate cancer cells, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 induced signaling events leading to MMP-9 expression, migration and invasion. CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface mediates these invasive signaling events and subsequent expansion of the skeletal metastatic deposits. Herein, we tested the efficacy of CXCR4 antagonist CTCE-9908 in prostate cancer cell growth, invasion, and metastasis. Methods: We used in vitro growth and invasion assays and in vivo orthotopic model system to asses the tumor growth and metastasis. Results: We found that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 cells; (b) CTCE-9908 compound at 50 μg/ml inhibited CXCL12 mediated invasion of PC-3 cells; (c) in vivo CTCE-9908 compound did not significantly altered the growth of primary tumors as measured by calipers and (d) the total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues were significantly decreased upon CTCE-9908 administration. Histological analysis showed that CTCE-9908 treatment resulted in tumor necrosis in primary prostate tumors. Conclusions: These data suggest that CXCR4 inhibition by CTCE-9908 compound decreased the invasive signaling and metastatic spread of tumor cells without apparently affecting the primary tumor growth in animal model. Hence, CTCE-9908 is an efficacious antagonist for CXCL12/CXCR4 signaling pathway mediating invasive spread of tumor cells in secondary metastasis formation. Studies of CTCE-9908 in phase II are planned.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 716.