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 Ca 2+ 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.

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

“…Previously, an orthotopic mouse model of BrM using triple-negative cell lines MDA-MB-231 and 4T1 have been reported in NSG and BALB/c mice, respectively, which are suitable for therapeutic modalities against TNBC [ 49 , 50 , 51 , 52 ]. In the ERBB2 + BC subtype, both intracardiac and intracarotid models have been used for the evaluation of therapeutic modalities against BC BrM [ 24 , 25 , 53 ]. However, neither of these models are enough to understand the mechanisms of BC progression and metastasis, nor can they be used to test preventative therapies in BC.…”

“…Mechanistically, our findings show that combination therapy profoundly downregulated the MAPK/ERK pathway, which is downstream to c-MET and ERBB1 pathways. Previous studies have highlighted the MAPK/ERK pathway as a key mediator of proliferation and metastasis in metastatic BC that together with AKT/mTOR and STAT3 plays an essential role in progression of BrM [ 53 , 68 , 69 ]. A recent study showed that NER monotherapy inhibits proliferation of ERBB2 + BC via inhibition of ferroptosis [ 20 ].…”

EMT related circular RNA expression profiles identify circSCYL2 as a novel molecule in breast tumor metastasis

“…In McF-7 cells, KEGG analysis con sistently revealed various signaling pathways involved in regulating tumor growth, such as 'TNF signaling pathway', 'Steroid hormone biosynthesis', 'NF-κB signaling pathway' and 'PI3K-AKT pathway'. Similarly in MDA-MB-231 cells, pathways such as 'ECM-receptor interaction' and 'Calcium signaling pathway' were enriched, which were reported to be associated with tumor cell proliferation and migration (27)(28)(29)(30)(31).…”

Is the Electrohypersensitive Patient's Headache a Variant of the Migraine Disease Mediated by TRPA1 Receptors?

“…It has been established that non-ionizing electromagnetic fields cause an increase in the concentration of intracellular free radicals in the human cell at sub-thermal thresholds (5,6). The mechanism of this increase, although debated, seems to be through the activation of voltage gate calcium channels (VGCCs) (7,8) . This increase in free radicals at the level of nociceptive neurons and in particular the trigeminal nerve one's would activate the Transient Receptor Potential A1 (TRPA1) (9) which causes the neuron to secrete CGRP Calcitonin Gene Related Peptide (CGRP)(10) and inflammatory molecules such as substance p and neurokinin as well as the release of histamine (11).…”