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Title: Metabolic profiling studies of tumour cell phenotypes
Author: Kelaini, Sophia
ISNI:       0000 0004 2696 9936
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Ovarian cancer is a devastating disease affecting millions of women worldwide. Initially successful chemotherapy using platinum-based drugs is often followed by a relapse after which platinum therapy is usually ineffective and prognosis poor. The mechanism by which platinum resistance develops and its reversal to a more sensitive phenotype are of major interest in modern medical oncology, especially for ovarian cancer which has overall low survival rates. In this study, different types of in vivo-derived and in vitro cell models of platinum resistance were examined within a metabolic context using ¹H NMR spectroscopy and bioinformatics-based approaches to test the hypothesis that a metabolic signature of a platinum resistance phenotype could be defined. The in vitro-derived cell models of platinum resistance focused on the study of the Mlh1 gene, whose loss of expression has been shown to play a role in the development of resistance to platinum drugs and mitochondrial dysfunction. A comparative metabolic analysis of a transient Mlh1 expression cell model (HEK-293T) involving kidney cell lines of common genetic background and the ovarian cancer cell lines A2780 and its platinum resistant sub-line CP70 of well-established Mlh1 status was conducted. This resulted in the definition of a metabolic signature associated with Mlh1 expression, which included metabolites such as glutathione, alanine, myo-inositol and phosphocholine. It also achieved to associate the loss of MLh1 to mitochondria. The in vivo-imitating cell model focused on the normoxic & hypoxic baseline metabolic profiling of isogenic ovarian cancer cells that were clinically sensitive (PEA1 and PEO1) or resistant (PEA2 and PEO4) to platinum. The ¹H NMR-generated results showed oxygen level-related changes in glucose, lactate, pyruvate, acetate, and choline-related metabolites. Overall, this study managed to contribute towards the understanding of platinum resistance in ovarian cancer through a metabolic spectrum using a variety of analytical and methodological tools.
Supervisor: Keun, Hector ; Gooderham, Nigel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral