Date of Award

2012

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Annette T. Byrne

Second Supervisor

Professor Jochen H.M. Prehn

Keywords

Glioblastoma, Therapy, Apoptosis

Abstract

Glioblastoma (GBM) is the most common and aggressive form of primary malignant brain cancer. Treatment options are limited due to tumour heterogeneity and invasive phenotype.

In order to develop more effective therapies, molecular characterisation of the disease is required along with the emergence of novel targeted therapies, with evidence to support a targeted pro-apoptotic response either alone or in combination with other therapeutic strategies. Critically, the role played by molecular imaging (Ml) in the development of novel therapeutic strategies for the treatment of GBM has gained increasing traction in recent years and has now emerged as an essential component of translational neuro-oncology research.

Firstly, within the currently presented thesis, the GBM and endothelial cell response to pro-apoptotic treatment with gossypol alone and in combination with temozolomide (TMZ) was investigated. Using in vitro cell-based assays, tumour and endothelial cells response to treatment was assessed. Findings indicate inhibition of GBM and endothelial cell viability, reduced angiogenesis and GBM cell invasion following combination therapy. Using a subcutaneous imageable GBM xenograft model, anti-proliferative, pro-apoptotic and antiangiogenic properties of the combination regimen were further observed.

Secondly, in order to enhance the utility of currently available GBM xenograft models, two second generation, clinically relevant and optically active in vivo models were developed and validated using a multi-modality imaging strategy. To this end, a novel combined dissociation/ transduction protocol was designed to facilitate lentiviral luciferase transduction of patient biopsy-derived GBM xvii Summary spheroids. Transduction had no direct effects on tumour histology or antitumour immunity.

Thirdly, the anti-GBM efficacy of the selective pro-apoptotic BH3 mimetic ABT- 263 alone and in combination with TMZ treatment was demonstrated in a cell line/ biopsy-derived GBM spheroid assay in vitro. Subsequently, sustained intracranial (i.e.) delivery of ABT-263 using ALZET® osmotic mini-pumps was investigated alone or in combination with systemic intraperitoneal (i.p.) administration of TMZ in a pilot study using the imageable GBM biopsy-derived xenograft model previously established. Intracranial surgical implantation of osmotic pumps to tumour bearing mice was shown to be associated with animal mortality. Further analysis of drug stability over time is warranted in order to fully elucidate ABT263 efficacy in a chronic local delivery setting.

In conclusion, application of a pro-apoptotic approach may represent a rational combination strategy arm for treating GBM in the clinic, thus targeting multiple ‘cancer hallmarks’. Evolution of new clinically relevant imageable disease models remains a key strategy for translational anti-GBM drug discovery

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

15.0 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2012.

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