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Ca2+ and CACNA1H mediate targeted suppression of breast cancer SB 203580 metastasis by AM RF EMF
Sambad Sharma a, Shih-Ying Wu a, Hugo Jimenez a, Fei Xing a, Dongqin Zhu a, Yin Liu a, Kerui Wu a, Abhishek Tyagi a, Dan Zhao a, Hui-Wen Lo a, Linda Metheny-Barlow b, Peiqing Sun a, John D. Bourland b, Michael D. Chan b, Alexandra Thomas c, Alexandre Barbault d, Ralph B. D'Agostino e, Christopher T. Whitlow f, Volker Kirchner g, Carl Blackman a, Boris Pasche a, Kounosuke Watabe a,
a Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America
b Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America
c Department of Hematology and Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America
d TheraBionic GmbH, Ettlingen, Germany
e Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America
f Department of Radiology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America
g Genolier Cancer Center, Genolier, Switzerland
Cav3.2 T-type channel
Background: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofre-quency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF).
Methods: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metas-tasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to an-imals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic under-pinnings associated with cancer inhibition was identified using an agnostic approach. Findings: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, ac-tivated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angio-genesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H.