Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Hebb, Matthew O.

2nd Supervisor

Schmid, Susanne

Co-Supervisor

Abstract

Glioblastoma (GBM) is the most common and lethal primary brain cancer in adults despite aggressive treatments with surgery and chemo-radiation. Advances in electrotherapeutics offer a foundation for developing new treatment modalities that exploit an innate vulnerability of glioblastoma (GBM). Low intensity, non-ablative electric fields are innocuous to normal neural structure, but incite GBM cell apoptosis by putatively disrupting cytokinesis and transmembrane ion homeostasis. Our collaborative research group is pioneering a new electrotherapeutic technology for GBM called Intratumoral Modulation Therapy (IMT) which uses customized, implanted bioelectrodes to deliver sustained, titratable and focused therapeutic electric fields into tumor-affected brain regions. My work has confirmed and expanded the group’s previous in vitro evidence of IMT efficacy against GBM and diffuse intrinsic pontine glioma (DIPG) and has demonstrated potent anti-neoplastic, pro-apoptotic effects of IMT in vitro without significant impact on non-cancerous post-mitotic neurons. The co-application of IMT also potentiates the benefits of chemotherapy and gene therapy. We have created a robust in vivo IMT model using allograft GBM cells in Fischer rats to test the efficacy of IMT in vivo. The GBM animal studies to date have demonstrated proof-of-concept efficacy of IMT against GBM using rudimentary, single-contact bioelectrodes. However, single-contact electrodes cannot adequately accommodate the entire tumor or GBM resection bed where recurrence is otherwise inevitable. In order to translate this technology to clinical use, new special purpose bioelectrodes must be designed and tested to optimize and contour IMT coverage. This thesis yielded key insight into the bioelectrode configuration and treatment settings for effective and safe IMT delivery in GBM and DIPG. Advances in this technology will facilitate clinical translation of IMT as a critically needed therapy for these devastating brain cancers.

Summary for Lay Audience

High-Grade Gliomas (HGG) are deadly brain tumors with very poor treatment outcomes. Glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are categorized as high-grade gliomas (HGGs) and remain among the most deadly brain cancers in adults and children, respectively. Treatment only extends life approximately 12 months, therefore research into new therapies is crucial. Our team has developed a new biotechnology called Intratumoral Modulation Therapy (IMT). This technology uses an implanted electrical system to treat and kill tumors within the brain. IMT has shown to be an effective first line treatment and enhances the effects of chemoradiotherapy. We hypothesized that IMT delivered via specially designed, implantable bioelectrodes within HGG tissue or resection cavity (where these tumors always recur in a short time after surgery) will slow HGG growth, kill tumor cells, and increase the sensitivity of HGG to standard chemotherapy and radiation. Advanced brain imaging techniques were used to assess tumor growth and survival alone and in combination with standard doses of chemotherapy and radiation. The clinical vision of IMT is to provide a concealed, anatomically focused, patient-specific therapy that can effectively fight these cancers and enhance the benefits of existing treatment options. The results of this project have provided key information used to advance IMT towards clinical application. The successful development of IMT technology has the potential to markedly improve the survival and quality of life for patients facing these deadly cancers.

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