Inhibition of murine osteosarcoma lung metastases using the CXCR4 antagonist, CTCE-9908.

256 Background The chemokine SDF-1 and its receptor, CXCR4, are involved in the regulation of metastases in many human tumors. Expression of CXCR4 in human osteosarcomas correlates with poor prognosis. SDF-1 is expressed at high levels in lung, bone marrow and liver, all of which are organs to which osteosarcoma can metastasize. These findings suggest that therapy that is aimed at disruption of this specific ligand/receptor complex may lead to a decrease in metastases. We utilized CTCE-9908, a SDF-1 analog and CXCR4 antagonist to determine whether inhibition of CXCR4 leads to a decrease in lung metastases in a murine model of osteosarcoma metastasis. Methods K7M2 murine osteosarcoma cells were pre-treated with CTCE-9908, or with T22, a different CXCR4 antagonist that has been shown to decrease lung metastases in a murine melanoma model. Control cells were treated with PBS. Following pre-treatment, 1x^6 cells were injected by tail vein into female Balb/C mice. Mice were then treated with CTCE-9908 subcutaneously, T22 intraperitoneally, or PBS, once daily x5, for 4 weeks. All animals were sacrificed on day 26 and the number of surface lung metastases counted. Results For the control mice, the average number of surface lung metastases was 9.9 (SD 7.3). Mice treated with CTCE-9908 had an average number of 3.4 nodules (SD 5.0, p-value 0.03). Interestingly, mice treated with T22 did not have a decrease in the number of nodules as compared to the control mice, 13.9 (SD 7.3, p-value 0.24). Conclusions Mice treated with the CXCR4 inhibitor, CTCE-9908, had a 67% decrease in the number of visible metastatic lung nodules. A phase I study of this compound in healthy adults did not reveal any significant toxicities. These results suggest that clinical studies of CTCE-9908 in human osteosarcomas may be warranted.