All ETDs from UAB

Advisory Committee Chair

Martin R Johnson

Advisory Committee Members

Ruiwen Zhang

Donald J Buchsbaum

L B Nabors

William B Parker

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma multiforme (GBM) is the most lethal form of primary brain neoplasm with average patient survival between 9 and 15 months even with the most aggressive treatment modalities. Unfortunately, this poor outcome has not appreciably changed in the past 50 years emphasizing the lack of traditional `trial and error' methods in identifying an efficacious treatment for GBM. Pharmacogenomics is greatly impacting cancer research through the development of personalized medicine and rationally designed treatment paradigms for the development of more efficacious and less toxic treatment modalities. The main objective of this research was to utilize a pharmacogenomic approach to identify new strategies for improved GBM therapy. We examined the molecular profiles of tumor tissues obtained from GBM patients with markedly different survival times, as well as non-neoplastic brain tissues, and identified any associations between gene expression with available demographic and clinical data. Furthermore, we investigated associations between gene expression profiles and patient outcome in response to capecitabine and radiotherapy. Results of this clinical study were further explored using in vitro and in vivo glioma models. The significant findings of this dissertation include: 1) identification of the potential GBM tumor-associated prognostic indicators survivin, TS, and USP10, 2) concurrent capecitabine and radiotherapy demonstrated comparable activity to the standard of care for GBM, 3) identification of significant associations between the expression of 24 genes involved in capecitabine metabolism and radiotherapy with patient outcome, 4) development of an 8 gene (RAD54B, FRAP1, DCTD, APEX2, TK1, RRM2, SLC29A1, and ERCC6) expression-based predictor model that accurately identified the clinical outcome of all patients examined, and 5) observation of a similar trend in expression for 21 of the 24 identified genes in capecitabine sensitive and resistant GBM xenograft models. These studies elucidated potential novel mechanisms underlying GBM biology and capecitabine response that may be useful in the design of efficacious GBM tumor-targeted therapies and capecitabine treatment regimens. Importantly, potential biomarkers of GBM patient prognosis and response to capecitabine were identified that may be used in the future stratification of patients towards more efficacious therapy.

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