Custom 3D Brain Cancer Model to Test a Novel Anti‐Cancer Electrotherapy

Abstract

IntroductionHigh‐Grade Gliomas (HGG) are primary malignant brain tumors with dismal treatment outcomes. Our team has been pioneering a novel implantable biotechnology called Intratumoral modulation therapy (IMT) that distributes non‐ablative electric fields across tumor‐affected brain regions to induce tumor cell death. A systematic means to define the mechanism and optimal treatment parameters for various forms of HGG is needed to advance this promising technology towards clinical application. The aim of this study was to develop a custom, high throughput, patient‐derived 3D HGG model to investigate the therapeutic effects of IMT.MethodsPrimary patient HGG cells (1×104) were implanted into wells of a 96‐well plate containing 200 uL of Matrigel®. The resultant tumor spheroids were characterized over 14 days by observing growth, invasion and viability with MTT assays, confocal microscopy and bioluminescence imaging (BLI). The culture plates were custom adapted to house implantable IMT devices to broadly distribute IMT fields across HGG tumors. Computer‐generated IMT field modeling was performed using COMSOL software to predict field strength and distribution, and to reconstruct IMT fields in the 3D system. Spheroids received 72‐hours of IMT using a spectrum of treatment parameters based upon a continuous, low amplitude sinusoidal waveform.ResultsPatient‐derived HGG spheroids exhibited multi‐layered, progressive growth and invasion of peritumoral matrix over the 14‐day study period. Computer simulation predicted electric field distribution and intensity across patient HGG spheroids for a spectrum of defined IMT parameters. Using the simulation plans to guide treatment settings, IMT produced a significant reduction (>60%) of metabolic viability in HGG spheroids treated with IMT compared to sham conditions. This data was corroborated by BLI which revealed >65% signal loss associated with IMT.ConclusionIMT is a highly promising innovation designed to combat HGGs, the most devastating of primary brain cancers. Our custom in vitro IMT model permits high throughput testing of treatment parameters in 3D patient HGG spheroids. This innovative preclinical strategy will be instrumental in defining the potential and optimizing treatment response across a spectrum of high fatality HGG cancers.Support or Funding InformationThis work was supported by the Cancer Research Society and preformed at Schulich School of Medicine and Dentistry and Lawson Health Research Institute.