Treatment with certain anti-cancer agents, particularly taxanes and sunitinib, can lead to mobilization of pro-angiogenic factors and an acute mobilization of endothelial progenitor cells (EPCs) and other stromal cells, which migrate to the viable tumor rim where they can enhance tumor vascularization, invasion and metastasis. This phenomenon has been linked to rapid tumor regrowth following chemotherapy or treatment with specific angiogenesis inhibitors and may thus diminish the long-term efficacy of the treatment. Stromal cells like EPCs are mobilized in response to circulating growth factors and chemokines (VEGFR, FGF, G-CSF, IL-6, SDF1α, etc.) that are induced by the drug or the progressing tumor. Many of these factors contain heparin binding domains for their anchorage to proteoglycans on cell surfaces or the extracellular matrix. We tested a novel heparan sulfate mimetic, M402, for its ability to inhibit EPC mobilization as well as tumor vascularization and invasion. Mice bearing orthotopic 4T1 breast carcinoma and treated with a single high dose of docetaxel (40 mg/kg) showed highly vascularized tumor rims by histology and Microfil perfusion followed by microCT (vessel volume of 5.8 ± 4.6 mm3 vs. 0.6 ± 0.3 mm3; vessel surface area of 153.9 ± 65.5 mm2 vs. 21.1 ± 6.7 mm2, respectively) as compared to the saline control group. The tumors also showed a higher rate of invasion through the peritoneal wall as compared to vehicle treated mice (5 of 16 mice vs. 2 of 16 mice, respectively). The effect correlated with mobilization of EPCs and other bone marrow derived stromal cells. Treatment with M402 did not show such a response but rather inhibited the effects of docetaxel when dosed concomitantly for 3-5 days, starting with the docetaxel administration. Analysis of the blood, tumor and bone marrow indicated that M402 prevented the mobilization of progenitor cells from the bone marrow and their recruitment into the tumor microenvironment, likely through disruption of the SDF-1α/CXCR4 axis. Furthermore, we observed synergistic anti-tumor and anti-metastatic activity of M402 with docetaxel in this 4T1 model. In conclusion, the experiments provide a rationale for the clinical investigation of M402 in combination with docetaxel or other agents that induce similar effects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2336. doi:1538-7445.AM2012-2336