Date on Master's Thesis/Doctoral Dissertation

8-2023

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Lehman, Norman

Committee Co-Chair (if applicable)

Clem, Brian

Committee Member

Clem, Brian

Committee Member

Klinge, Carolyn

Committee Member

Ceresa, Brian

Committee Member

Trent, John

Committee Member

Samuelson, David

Author's Keywords

glioblastoma; aurora kinase a; combination therapy; carboplatin; taxane

Abstract

Glioblastoma is the most common and aggressive central nervous system tumor in adults with a 6% survival rate. Decades of research for improving life expectancy and quality of life have been ineffective. The discovery of better treatment strategies is urgent to improve the survival rates for glioblastoma patients. Aurora Kinase A is a regulator of tumor progression and is overexpressed in glioblastoma. We used a specific Aurora Kinase A inhibitor alisertib in combination with DNA-damaging platinum agent carboplatin or brain-penetrating taxane TPI 287. We investigated the efficacy of these combinations in treating in vitro and in vivo tissue culture models of glioblastoma. We utilized a wide range of methods to study the mechanism of action of alisertib, carboplatin, and TPI 287 treatments, including cell lines with different molecular characteristics, RNA-sequencing, orthotopic xenograft mouse models, three-dimensional extracellular matrix-mimicking materials, and various biochemical and biophysical assays. Our results revealed that the alisertib and carboplatin combination had selectively higher efficacy in poor prognosis, O-6-methyl guanine methyltransferase (MGMT) expressing glioblastoma. We also identified MGMT expression had a substantial effect on the regulation of gene expression, primarily affecting the three-dimensional and in vivo growth of tumor cell lines. To our knowledge, this is the first publication reporting the effect of MGMT expression on response to alisertib and carboplatin combination treatment and gene expression. Our investigation as a mechanism of alisertib and carboplatin efficacy by the involvement of G-quadruplex secondary DNA structures was inconclusive. The experiments testing the combination of alisertib with TPI 287 showed promising results in treating cancer stem-like glioblastoma cell lines. We also found that alisertib and TPI 287 treatment converge on apoptosis regulating Bcl-2 family proteins, resulting in potentiated efficacy. Overall, these results show that Aurora Kinase A inhibition potentiates carboplatin or TPI 287 treatment which warrants further preclinical and clinical testing to understand the mechanisms and determine the potency in increasing glioblastoma patient survival rate. Identification of mechanisms of action allows the stratification of patients that will benefit from these treatment options. All in all, this approach is promising for glioblastoma patients without any effective treatment options.

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