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Title: Identification of novel targets to augment temozolomide potency in glioblastoma
Author: Carmell, Natasha
ISNI:       0000 0004 7651 4972
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Brain tumours kill more children and adults under 40 than any other cancer. Approximately half of primary brain tumours are high-grade malignancies called glioblastoma multiforme (GBM). The current treatment regime for GBM combines de-bulking surgery with radiotherapy and the chemotherapeutic temozolomide. However, mean survival for patients is approximately 15 months, with less than 5% achieving 5 year survival. Unfortunately, this devastating prognosis has improved little over the last 40 years, highlighting the need for new strategies to improve the treatment of these tumours. To identify potential novel drug targets that could augment the cytotoxicity potency of temozolomide, a dual approach was taken in temozolomide resistant T98G GBM cells; a kinome-wide siRNA screen and two small molecule repurposing drug screens. Cell viability was calculated by high-content microscopy and algorithmbased scoring of Hoechst-positive cells. Target validation studies were carried out using additional siRNA libraries and small-molecule compound dose-escalation studies in additional GBM cell lines and primary glioma stem-like cultures. These screens identified the targeting of Extracellular Regulated Kinase 5 (ERK5) or Fibroblast Growth Factor Receptor 4 (FGFR4), as well as the use of butamben to augment temozolomide sensitivity. We also find that ERK5 is upregulated (mRNA and protein) in GBM compared to normal brain tissue, offering a potential therapeutic window for tumour specificity. Furthermore, the combination of EKR5 inhibition and temozolomide caused an increase in DNA damage combined with a reduction in homologous recombination and an increase in non-homologous end joining, likely to be potentiated through mitotic progression, inducing chromosomal aberrations and heightened cell death. These exciting data provide a platform for further pre-clinical and clinical investigation into these strategies as a means to improve the treatment options for GBM patients.
Supervisor: Collis, Spencer J. ; El-Khamisy, Sherif Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available