ATPS-30INTRATUMORAL MODULATION THERAPY FOR GLIOBLASTOMA

Abstract

BACKGROUND: There is a critical need for innovative and effective treatment strategies for glioblastoma (GBM). The clinical indications for neuromodulation therapy in the brain are rapidly expanding and this technique is now the standard of surgical care for select neurological diseases (e.g., Parkinson's Disease). It is well known that glial tumors are vulnerable to perturbations of the electrochemical environment; however, direct neuromodulation techniques have not been exploited for glioma management. METHODS: Our group has developed an in vitro model to deliver continuous alternating or pulsed, low voltage electric current directly into GBM cultures, a technique we call intratumoral modulation therapy (IMT). GBM cell lines and primary GBM cells derived from operative specimens were studied for vulnerability to IMT without and with temozolomide (TMZ) or oncogene-targeting strategies. An F98 rat GBM model has also been established to evaluate the benefits of IMT in vivo. RESULTS: We report a marked vulnerability of patient GBM cells, but not primary neurons, to a spectrum of IMT parameters. GBM cells treated with IMT undergo enhanced caspase 3-activation and apoptosis, and develop heightened sensitivity to TMZ. Uptake and biodistribution of siRNA was enhanced in primary GBM cells, along with target gene knockdown and functional effect, in the presence of IMT. Preliminary in vivo studies indicate that IMT markedly attenuates GBM growth without significant treatment-related morbidity. CONCLUSIONS: The proposed use of minimally invasive implantable stimulation devices offers distinct advantages over existing electrotherapies, including direct lesion targeting for delivery of continuous IMT, titratible stimulation settings to maximize benefit and lessen off-target effects and low maintenance, concealed hardware for improved self-perception and quality of life. Results from these investigations provide proof of principle evidence that supports further evaluation of IMT for the treatment of GBM.