Abstract LB-95: Inhibition of CXCR4/Stat3 signaling by AMD3465 exerts major tumor- and metastasis-suppressive effects in syngenic 4T1 breast cancer model

Abstract

Abstract Stromal-derived factor-1 α (SDF-1α, also termed CXCL12) and its receptor CXCR4 have been shown to play important roles in hematopoietic stem cell homing, and high expression of CXCR4 has been associated with poor prognosis in hematologic malignancies. The CXCR4/SDF-1α axis is also functional in solid tumors, including breast cancer. It has been postulated that Stat3 may promote metastases in breast cancer through direct interaction with CXCR4, promoting tumor growth and survival. Phosphorylated Stat3 was found to trigger overexpression or activation of several potent oncoproteins. In order to evaluate the role of CXCR4 in metastases, we used the specific CXCR4 inhibitor, AMD3465, to block CXCR4 in the syngeneic 4T1 breast cancer model. Stat3, Akt, Erk1/2, Jak2 and MMP9 activity was found to be almost completely inhibited and expression levels of GSK-3β and cMyc were greatly reduced. Growth of 4T1 cells orthotopically implanted into the mammary fat pad as well as pulmonary and liver metastases were significantly (>95%) reduced in vivo when AMD3465 was given as continuous infusion at a dose of 428.57μg/mouse/day over 14 days. Furthermore, we observed that CXCR4 inhibition by AMD3465 significantly reduced lung metastases in three immunocompetent syngeneic mouse models after surgical resection of the primary breast tumors. This experimental design mimics current clinical treatment strategies. Kozin et al. (Cancer Research 70: 5679–85; 2010) recently suggested that CD11b+ myeloid/monocytic cells (a cell type implicated in supporting angiogenesis) may play a role in tumor re-growth in response to SDF-1 α. In support of this observation, we observed significantly reduced CD11b+ cells in lungs, livers and spleens (P<0.01 for all 3 organs) following treatment with AMD3465, as compared to PBS controls. Hence, our data suggest that pharmacological CXCR4 inhibition in breast cancer-bearing mice following primary tumor resection is well tolerated and potently controls the development of distant metastatic lesions. In conclusion, interruption of the SDF-1/CXCR4/Stat3 signaling axis by the CXCR4-specific inhibitor, AMD3465, effectively inhibits pulmonary and hepatic breast cancer metastasis via disruption of intracellular microenvironment mediated signaling in breast cancer cells and through effects on CD11b+ tumor infiltrating myeloid cells. 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-95. doi:10.1158/1538-7445.AM2011-LB-95