All ETDs from UAB

Advisory Committee Chair

Christopher D Willey

Advisory Committee Members

Etty Benveniste

Lawrence J Delucas

George Y Gillespie

N Rama Krishna

Kirill M Popov

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma multiforme (GBM) is the most common and deadly primary brain malignancy necessitating improved understanding of GBM biology. In this study, we explore the role of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) in the context of GBM. We have discovered that the MARCKS protein regulates GBM growth as well as response to radiation therapy through its effects on proliferation, senescence, and DNA repair based on our studies in cell culture and in patient-derived xenograft tumors implanted in mice. Importantly, our analysis of clinical patient data demonstrates that MARCKS is an independent predictor for outcome in GBM patients. Indeed, high MARCKS levels promoted improved outcomes, which was consistent across our model systems. We then utilized a compound library from the National Cancer Institute's Developmental Therapeutics Program for an in silico drug screen to identify potential MARCKS modulators. We identified the compound Rutoside and further characterized its interaction with the MARCKS effector domain by Nuclear Magnetic Resonance Studies. Our results suggest that MARCKS may be a biomarker for prognosis as well as a potential target for therapy in GBM and Rutoside may be a novel agent for this purpose.

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