Abstract 4116: A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton

Abstract

Abstract Therapeutic approaches aimed to prevent breast cancer cells from spreading to distant sites are commonly neglected, based on the indication that dissemination from primary tumors can occur early. However, mounting evidence indicates that cancer cells recirculating from established bone lesions could further seed and colonize both skeleton and soft-tissue organs, thus precipitating metastatic dissemination and accelerating disease progression. We have previously shown that breast circulating tumor cells (CTCs) rely on the chemokine receptor CX3CR1 for lodging to the skeleton. Here, we show that this receptor is overexpressed by all four main subtypes of breast adenocarcinoma and also abundantly detected in bone metastatic lesions from breast cancer patients. We have recently synthesized JMS-17-2, a novel small molecule inhibitor of CX3CR1. We tested this compound in pre-clinical animal models of metastases in which human breast cancer cells, labeled with fluorescent and bioluminescent markers, are converted into CTCs by direct grafting in the arterial blood circulation. Pre-incubating cancer cells with JMS-17-2 or treating animals with this compound (10 mg/Kg, i.p.) were equally effective in dramatically decreasing the number of breast CTCs that lodged to the skeleton. These disseminated tumor cells (DTCs) were detected 24 hours after grafting and enumerated by multispectral fluorescence microscopy of sequential bone tissue sections spanning the entire width of tibiae and femora. Notably, when animals were examined at two weeks after grafting, JMS-17-2 completely prevented metastases, indicating that the reduction in number of DTCs directly translates to an impaired tumor growth in the long term. Finally, JMS-17-2 was administered to animals harboring a limited number of small metastases in bone and soft-tissues and monitored by bioluminescence imaging for three weeks before sacrifice. Animals treated with the CX3CR1 antagonist remained at an oligometastatic stage whereas control animals showed a sharp increase in the number of metastatic lesions and overall tumor burden. The work presented here should generate a conceptual shift in the treatment strategies for breast cancer patients, paving the way to approaches aimed to counteract the seeding of additional lesions from existing metastases. We also introduce JMS-17-2 as the first CX3CR1 antagonist and lead compound of a class of potentially new drugs with a novel mechanism of action that could be added to the arsenal of therapies currently used to treat advanced breast adenocarcinoma. Citation Format: Fei Shen, Yun Zhang, Danielle Jernigan, Jie Yan, Fernando Garcia, Olimpia Meucci, Joseph Salvino, Alessandro Fatatis. A small-molecule antagonist of CX3CR1 impairs homing and colonization of breast cancer cells in the skeleton. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4116. doi:10.1158/1538-7445.AM2015-4116