ABSTRACT
The lack of treatment options for high-grade brain tumors has led to searches for alternative therapeutic modalities. Electrical field therapy is one such area. The Optune™ system is an FDA-approved novel device that delivers continuous alternating electric fields (tumor treating fields-TTFields) to the patient for the treatment of primary and recurrent Glioblastoma multiforme (GBM). Various mechanisms have been proposed to explain the effects of TTFields and other electrical therapies. Here, we present the first study of genome-wide expression of electrotherapy (delivered via TTFields or Deep Brain Stimulation (DBS)) on brain tumor cell lines. The effects of electric fields were assessed through gene expression arrays and combinational effects with chemotherapies. We observed that both DBS and TTFields significantly affected brain tumor cell line viability, with DBS promoting G0-phase accumulation and TTFields promoting G2-phase accumulation. Both treatments may be used to augment the efficacy of chemotherapy in vitro. Genome-wide expression assessment demonstrated significant overlap between the different electrical treatments, suggesting novel interactions with mitochondrial functioning and promoting endoplasmic reticulum stress. We demonstrate the in vitro efficacy of electric fields against adult and pediatric high-grade brain tumors and elucidate potential mechanisms of action for future study.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/therapy , Brain/pathology , Cell Proliferation/genetics , Cell Line, Tumor , Cell Survival/genetics , Child , Combined Modality Therapy/methods , Electric Stimulation Therapy/methods , Endoplasmic Reticulum Stress/genetics , G2 Phase/genetics , Glioblastoma/genetics , Glioblastoma/therapy , Humans , Mitochondria/genetics , Resting Phase, Cell Cycle/geneticsABSTRACT
The standard of care for patients with newly diagnosed Glioblastoma multiforme (GBM) has remained unchanged since 2005, with patients undergoing maximal surgical resection, followed by radiotherapy plus concomitant and maintenance Temozolomide. More recently, Tumour treating fields (TTFields) therapy has become FDA approved for adult recurrent and adult newly-diagnosed GBM following the EF-11 and EF-14 trials, respectively. TTFields is a non-invasive anticancer treatment which utilizes medium frequency alternating electric fields to target actively dividing cancerous cells. TTFields selectively targets cells within mitosis through interacting with key mitotic proteins to cause mitotic arrest and cell death. TTFields therapy presents itself as a candidate for the combinational therapy route due to the lack of overlapping toxicities associated with electric fields. Here we review current literature pertaining to TTFields in combination with alkylating agents, radiation, anti-angiogenics, mitotic inhibitors, immunotherapies, and also with novel agents. This review highlights the observed synergistic and additive effects of combining TTFields with various other therapies, as well highlighting the strategies relating to combinations with electric fields.
