Abstract
Abstract Brain metastasis is evident in approximately 30% of patients with breast cancer and one-year survival of these patients remains less than 20%. The treatment of brain metastasis mainly involves surgical resection in combination with whole brain radiation therapy (WRBT), or stereotactic radiosurgery (SRS). However, patients often suffer from the treatment’s adverse effects and experience recurrent disease. Therefore, there is an urgent need for a less invasive therapy with minimal side effects, and improved therapeutic efficacy. Our current work has established a novel treatment approach for breast cancer brain metastasis at a preclinical level by using amplitude modulated radiofrequency electromagnetic fields (AM RF EMF). We have previously demonstrated that AM RF EMF can be safely administered to patients for prolonged period of time with virtually no toxicity and side effects. The treatment of metastatic breast cancer patients with AM RF EMF significantly impaired the growth of both metastatic and primary tumor (1). In this study, we specifically observed the effect of AM RF EMF in brain metastatic variants of breast cancer cells (231-BrM and SKBr-BrM). We found that AM RF EMF significantly inhibited the growth, stemness and colony forming ability of brain metastatic variants of breast cancer cells. In addition, AM RF EMF inhibited the stemness of radiation resistant variants derived from 231-BrM and SKBr-BrM cells, which indicate the potential of AM RF EMF in treatment of treatment-refractory recurrent disease. Furthermore, AM RF EMF also significantly suppressed the growth of orthopically and systemically implanted 231-BrM and SKBr-BrM cells in our NOD/SCID animal model. We then performed RNAseq expression profile analysis and found that expression of stemness-associated gene, HMGA2, was significantly decreased in 231-BrM and SKBr-BrM cells that were treated with AM EMF RF. Interestingly, brain metastatic variants and radiation resistant lines of 231-BrM and SKBr-BrM showed elevated expression of HMGA2 when compared to their parental cells. Importantly, the treatment of brain metastatic cells with AM RF EMF also sensitized the cells to radiation in a HMGA2 dependent manner. Furthermore, to isolate the AM RF EMF responsive biomarker, we isolated exosomes from the SKBr-BrM cells that were treated with AM RF EMF, and performed microRNA array. Differentially expressed miRNAs in SKBr-BrM and 231-BrM cells derived exosomes were identified and verified by Taqman PCR. These exosomal microRNAs can serve as excellent biomarkers for examining the effect of AM RF EMF in brain tumors. Therefore, our study has demonstrated that this new approach of treating brain metastasis has a high translational potential considering significant efficacy and minimal side effect shown in pre-clinical and clinical setting. Citation Format: Sambad Sharma, Hugo Jimenez, Fei Xing, Carl Blackman, Boris Pasche, Kounosuke Watabe. Breast cancer-specific amplitude modulated radiofrequency electromagnetic fields (AM RF EMF) inhibits brain metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5207. doi:10.1158/1538-7445.AM2017-5207
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