A CSF-1R inhibitor both prevents and treats triple-negative breast cancer brain metastases in hematogenous preclinical models

Abstract

Brain metastasis is a common and serious complication of metastatic triple-negative breast cancer (TNBC) with few effective treatments. Here, we evaluated the effect of targeting the brain tumor microenvironment via the myeloid colony-stimulating factor-1 receptor (CSF-1R) pathway using the small molecule inhibitor BLZ945. Studies were conducted in two TNBC hematogenous brain-tropic models, 4T1-BR5 and 231-BR, with endpoints of prevention of brain metastasis formation and treatment of established brain metastasis. BLZ945 reduced the formation of brain metastases in both models by 57–65% (all p < 0.01) in the prevention setting. In the treatment setting, more analogous to the clinical situation, BLZ945 reduced the number and size of metastases in both models by 44–65% and 61–72%, respectively (all p < 0.05). Treatment with BLZ945 significantly reduced the number of myeloid cells in both the uninvolved brain and metastatic regions, by 15–54% across models as early as three days post-treatment. Efficacy was achieved without the need for complete suppression of brain myeloid cells, suggesting that potential adverse effects of full myeloid suppression can be minimized. Additionally, BLZ945 reduced cancer cell proliferation and astrocyte activation in the tumor microenvironment in vivo . In vitro studies showed that BLZ945 inhibited the secretion of inflammatory cytokines that stimulated cancer cell invasion; BLZ945 also indirectly reduced cancer cell proliferation through astrocyte interaction. Our findings suggest that microglial CSF-1R controls a series of myeloid regulatory pathways, both alone and in concert with other brain microenvironmental cells. The data preclinically credential CSF-1R inhibition as a potential therapeutic strategy for TNBC brain metastases.

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