Abstract 1071: Efficacy of targeted osmotic lysis using pulsed electric field stimulation compared to paclitaxel for treating murine, triple-negative breast carcinoma
Authors: Gould Harry J. , Sherman Kelly J. , Paul Dennis 
Published: June 2022

Abstract
Targeted osmotic lysis (TOL), the concurrent stimulation of voltage-gated sodium channels (VGSCs) and blockade of Na+ pumps, kills up to 100% of highly malignant, human and murine breast cancer cells in vitro and slows the growth of murine breast cancer homografts and increases survival of the hosts in vivo when compared to homografts treated with negative controls. In this study we compared the efficacy of TOL and paclitaxel, a current standard chemotherapeutic agent for treating advanced murine breast cancer, as a positive control. For this, BALB/c mice with 4T1 homografts were treated with TOL alone, paclitaxel alone or with a combination regimen of paclitaxel and TOL. For TOL, mice received 8 hourly doses (3 mg/kg) of digoxin on 2 successive days. Upon reaching steady-state levels (dose 5) the mice were exposed to 4 X 30 minutes of pulsed electric field stimulation (18 V/m, 10 ms pulses, 15 interstimulus intervals) hourly for a total of 2 hours of stimulation. Alternatively, mice received paclitaxel (20 mg/kg) by i.p. injection. Mice that were treated concurrently with TOL and paclitaxel received paclitaxel 2 days prior to treatment with TOL. Groups of mice that received digoxin alone, stimulation alone, paclitaxel + digoxin, paclitaxel + stimulation or vehicle alone served as negative controls. Initially, the homografts were measured daily and then every other day with a digital caliper until criteria for humane endpoint euthanasia were met. The mean time to meeting criteria for humane endpoint euthanasia in mice treated with paclitaxel alone (2 days) was identical to that observed in the negative controls. Mice treated with TOL alone, on average, met criteria at post-treatment day 5, whereas administration of paclitaxel two days before TOL reduced the effectiveness of TOL, decreasing mean survival to day 3 post-treatment. Immunohistochemical evidence indicated that paclitaxel’s effect on tubulin may impede the transport and insertion of channels into the cell membrane, thereby reducing the channel density and the effectiveness of TOL. By contrast, the administration of TOL either before or after treatment with paclitaxel improved host survival. Normal tissues were unaffected. These results are evidence that TOL is equal to or better than paclitaxel for increasing survival of murine hosts with advanced breast cancer when TOL is administered before or between paclitaxel dosing cycles. Sequential use of TOL may well improve survival, but simultaneous administration of paclitaxel and TOL will likely reduce TOL’s adjunctive benefit. Because of the conserved nature of the sodium channel/sodium pump mechanism, the comparable efficacy to TOL to a currently approved treatment and the favorable adverse effect profile, we submit that TOL warrants further study as a promising option for treating individuals with advanced neoplastic disease.
Citation Format: Harry J. Gould, Kelly J. Sherman, Dennis Paul. Efficacy of targeted osmotic lysis using pulsed electric field stimulation compared to paclitaxel for treating murine, triple-negative breast carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1071.