Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

W Mark Saltzman

Subject Area(s)

Biomedical engineering, Neurosciences, Oncology

Abstract

Glioblastoma multiforme is the most common malignant primary intracranial tumor in adults. Despite years of advances in basic science knowledge about this disease including but not limited to cellular hierarchy, genetics, and mechanisms of proliferation and spread, overall survival of patients has remained unmoved for the past fifteen years, and long-term survivors are nearly nonexistent. Barriers to improved treatment occur in the realms of engineering and drug discovery: creation of an efficient delivery vehicle and identification of novel, efficacious small molecule compounds are necessary to achieve survival benefit in this disease.

In the following thesis, I describe efforts made by myself individually and alongside members of the laboratory of W Mark Saltzman, PhD, Goizueta Foundation Professor and Chairman of Biomedical Engineering, to test a novel, highly-penetrative polymeric nanocarrier platform for intracranial drug delivery and develop a high-throughput screen for small molecule compounds with efficacy against brain cancer stem cells. I show that the combination of the efficient delivery system and small molecule compounds with efficacy against brain cancer stem cells produces unprecedented gains in survival in a rat model of glioblastoma. Further, I describe the design and quality control methodology of the high-throughput small molecule screen and identify a large number of small molecule compounds with equal efficacy to first-generation anti-brain cancer stem cell drugs with fewer safety concerns. Together, the data underscore a) the promise of this efficient delivery vehicle to rapidly test the identified anti-brain cancer stem cell compounds and b) the potential for this combination to revolutionize glioblastoma therapy.

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