Abstract
Abstract Biomarkers associated with systemic inflammation correlate with poor prognosis in cancer patients. Circulating cell-free DNA (cfDNA) is released passively and actively by both tumor cells and host cells and cfDNA levels in blood correlate with tumor burden in many tumor types. Notably, studies in breast cancer have shown that inhibition of cfDNA has a significant effect in reducing invasion and migration in vitro and metastatic disease in vivo. We have previously demonstrated that nucleic acid binding polymers (NABPs) bind and inhibit the proinflammatory effects of cfDNA in a murine model of pancreatic cancer. We observed that levels of cfDNA in blood increase with tumor burden in an orthotopic immunocompetent murine model of breast cancer. Moreover, treatment of mice with the NABP, PAMAM-G3, following surgical removal of primary tumor results in decreased lung metastasis. This decrease in lung metastasis is associated with reduction in the levels of cfDNA in blood. In addition, treatment of mice with NABPs in an intravenous experimental metastasis breast cancer model results in reduced seeding of tumor cells in lungs and lung metastasis. Analysis of immune infiltrates in lungs of PAMAM-G3- and control-treated mice demonstrates NABP-mediated transition of immune cell composition in lungs from innate to adaptive immune cells. Collectively, these data suggest that NABPs can be used to target cfDNA and inhibit DAMPs associated pathological inflammation. The use of NABPs is an innovative approach to treat cancer progression and metastasis, particularly in a clinical setting following standard of care surgical tumor resection. This work is funded by the Department of Defense Breast Cancer Research Program award (PI, Smita Nair).
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