Ca2+ and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMF.

Abstract

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 radiofrequency 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 metastasis 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 animals 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 underpinnings 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, activated 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 angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H.

INTERPRETATION:

We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.

• Authors: Sambad Sharma, Shih-Ying Wu, Hugo Jimenez, Fei Xing, Dongqin Zhu, Yin Liu, Kerui Wu, Abhishek Tyagi, Dan Zhao, Hui-Wen Lo, Linda Metheny-Barlow, Peiqing Sun, John D Bourland, Michael D Chan, Alexandra Thomas, Alexandre Barbault, Ralph B D'Agostino, Christopher T Whitlow, Volker Kirchner, Carl Blackman, Boris Pasche, Kounosuke Watabe
• Journal: EBioMedicine (EBioMedicine) Vol. 44 Pg. 194-208 (Jun 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 31129098 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• CACNA1H protein, human
• Calcium Channels, T-Type
• HMGA2 Protein
• Calcium

Topics

• Animals
• Brain Neoplasms (diagnosis, metabolism, secondary, therapy)
• Breast Neoplasms (metabolism, pathology)
• Calcium (metabolism)
• Calcium Channels, T-Type (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Disease Models, Animal
• Electromagnetic Fields
• Female
• Gene Expression Profiling
• HMGA2 Protein
• Humans
• Immunohistochemistry
• MAP Kinase Signaling System
• Magnetic Field Therapy (methods)
• Mice
• Models, Biological
• Neoplastic Stem Cells (metabolism)