Date

9-1-2013

Document Type

Thesis

Degree Name

Ph.D.

Department

Dept. of Biomedical Engineering

Institution

Oregon Health & Science University

Abstract

Glioblastoma Multiforme is the most aggressive manifestation of glioma, affecting ~12000 people/year in the United States alone, with an average survival of just 12-14 months. Despite robust vascularization in malignant gliomas, anti-angiogenic therapy has failed to induce durable responses. This can be attributed, at least in part, to the upregulation of resistance mechanisms such as the pro-survival Akt pathway and its downstream effects on autophagy and cell growth. This dissertation aims at improving the anti-tumor and anti-angiogenic efficacy of the receptor tyrosine kinase inhibitor, cediranib (targets include vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptors) in the treatment of glioblastoma. Studies were focused on two novel therapeutic combinations with cediranib, which have the potential to modulate the Akt pathway and its downstream targets and create a synergistic anti-glioma effect. Because autophagy (a cellular catabolic pathway) can promote tumor cell survival and resistance, the first therapeutic strategy involved a combination of cediranib with the late stage autophagy inhibitor, quinacrine. A combination of biophysical techniques and magnetic resonance imaging revealed enhanced glioma cytotoxicity in vitro and a potent reduction in tumor growth and vascularization in vivo, accompanied by increased tumor necrosis and median survival. The second therapeutic strategy involved a novel combination of cediranib with proteasome inhibitor, SC68896. Results described in this thesis demonstrate a significant improvement in anti-glioma efficacy for this combination, and also a possible normalizing effect on the tumor vasculature. Collectively, this thesis provides insights into the potential for two innovative treatment strategies for malignant glioma and warrants further exploration in the clinical setting.

Comments

This document has been embargoed indefinitely and consequently is not available in full text electronic format. A circulating bound text of the document is available in the stacks of the Library.

Identifier

doi:10.6083/M4W9576G

School

School of Medicine

Available for download on Friday, December 31, 9999

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