Abstract LB-387: Blockade of the CXCL12/CXCR4 axis with AMD3100 induces multimodal antitumor effects in murine ovarian cancer and prolongs survival

Abstract

Abstract The chemokine, CXCL12, and its receptor, CXCR4, have been shown to be expressed by various tumors including ovarian cancer. CXCL12/CXCR4 expression by tumors has been associated with enhanced progression including tumor cell proliferation, invasion, and angiogenesis. We proposed that modulation of the CXCL12/CXCR4 axis in ovarian cancer would have multimodal effects on tumor pathogenesis. This was addressed using RNAi technology and a selective CXCR4 antagonist, AMD3100, in an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer derived from a syngeneic cell line (BR5–1) that constitutively expresses both CXCL12 and CXCR4. CXCL12 knockdown of BR5–1 cells using RNAi reduced cell proliferation in vitro (p<0.01) and tumor growth in vivo (p<0.05) compared to controls. AMD3100 treatment of BR5–1-derived tumors resulted in the increase of tumor apoptosis (p<0.05)and necrosis and in a significant reduction of intraperitoneal dissemination, angiogenesis, and intratumoral infiltration of FoxP3+ regulatory T cells compared to controls (T-regs)(p < 0.05). In addition, selective CXCR4 blockade with AMD3100 resulted in significantly increased anti-tumor T cell mediated immune responses compared to controls (p<0.05). These multimodal anti-tumor effects translated into a significant survival advantage in AMD3100-treated mice as compared to controls (p<0.05). Selective CXCR4 antagonism also significantly decreased intratumoral T-regs infiltration in a second model of aggressive melanoma (p<0.05). In summary, these data generated in an immunocompetent syngeneic and orthotopic murine model of ovarian cancer lend important support to the view that the CXCL12/CXCR4 axis plays multiple roles in the pathogenesis of this disease. Furthermore, the availability of a safe, effective and clinically applicable CXCR4 antagonist in AMD3100 adds both to the direct clinical translatability of this study and to the potential for the use of this agent as an adjunct to conventional chemotherapy or in combination with other immunotherapies aimed at enhancing CD8+ T cell responses in human ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-387. doi:10.1158/1538-7445.AM2011-LB-387