Characterization of Ablation Thresholds for 3D-Cultured Patient-Derived Glioma Stem Cells in Response to High-Frequency Irreversible Electroporation.

J W Ivey,E M Wasson,A Kanitkar,R V Davalos,W Debinski,N Alinezhadbalalami,Z Sheng,S S Verbridge

doi:10.34133/2019/8081315

Abstract

High-frequency irreversible electroporation (H-FIRE) is a technique that uses pulsed electric fields that have been shown to ablate malignant cells. In order to evaluate the clinical potential of H-FIRE to treat glioblastoma (GBM), a primary brain tumor, we have studied the effects of high-frequency waveforms on therapy-resistant glioma stem-like cell (GSC) populations. We demonstrate that patient-derived GSCs are more susceptible to H-FIRE damage than primary normal astrocytes. This selectivity presents an opportunity for a degree of malignant cell targeting as bulk tumor cells and tumor stem cells are seen to exhibit similar lethal electric field thresholds, significantly lower than that of healthy astrocytes. However, neural stem cell (NSC) populations also exhibit a similar sensitivity to these pulses. This observation may suggest that different considerations be taken when applying these therapies in younger versus older patients, where the importance of preserving NSC populations may impose different restrictions on use. We also demonstrate variability in threshold among the three patient-derived GSC lines studied, suggesting the need for personalized cell-specific characterization in the development of potential clinical procedures. Future work may provide further useful insights regarding this patient-dependent variability observed that could inform targeted and personalized treatment.

Highlights

Glioblastoma (GBM), the most common and deadly primary brain tumor, has a dismal prognosis that has remained relatively unchanged despite decades of research [1]
Because we have previously demonstrated that nuclear size is strongly correlated with High-frequency irreversible electroporation (H-FIRE) cell damage, we further hypothesize that will glioma stem-like cell (GSC) be susceptible to H-FIRE damage, and this susceptibility may be enhanced compared with normal cell types such as astrocytes, which possess normal nuclear size
These measurements were compared to similar measurements taken of established differentiated U-251 MG GBM cells and nonmalignant human astrocytes (NHAs) as well as nonmalignant human neural stem cells (NSCs) (Figure 1)

Summary

Introduction

Glioblastoma (GBM), the most common and deadly primary brain tumor, has a dismal prognosis that has remained relatively unchanged despite decades of research [1]. A GBM tumor proves fatal within about 14 months even with multimodal intervention [2]. GBM tumors are treated with surgery followed by concurrent radiotherapy and adjuvant chemotherapy [3,4,5]. Neither single therapies nor treatments used in combination are curative and they are often debilitating to the patient. The failure of current treatments to greatly extend life expectancy is attributable, among other reasons, to several classes of therapy-resistant cells that propel tumor recurrence, which is nearly universal with GBM [6]. There exists a real need for next-generation GBM therapies, for use alone or in combination with current therapies, which can target the resistant cell populations and prevent tumor recurrence

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