Analysis of the molecular basis of individuality in RTK pathway expression in human ovarian tumours – identification of patient selection biomarkers for personalised cancer medicine

Growth factors (e.g. EGF, FGF, PDGF, VEGF) and associated receptor tyrosine kinases (RTKs) regulate key signal transduction pathways which are frequently dysregulated in cancer. RTK pathways are common targets in chemotherapy drug development, but optimal patient selection and drug efficacy is often limited by lack of target specificity. We have compared growth factor and RTK expression in human ovarian tumours, described marked inter-individual differences in gene expression, and identified significant associations comparing gene expression with tumour histology, patient survival and chemotherapy response (1). We have also analysed growth factor expression in ovarian tumour cell lines, identified cell lines which mimic expression in human ovarian tumours, and created stable daughter lines with variable levels of RTK pathway knockdown. We therefore have access to both clinical samples and unique experimental models with which to further explore the functional and clinical consequences of variation in RTK expression in ovarian cancer. New developments in chemotherapy drug design reflect the move to more “personalised” treatment, where drug selection is increasingly tailored to patient genotype or phenotype. Alterations in RTK signaling are common to the majority of solid tumours, and these pathways are important drug targets for existing chemotherapy drugs and new agents in development. In this project, we will use a variety of experimental approaches to perform detailed analysis of growth factor signaling pathways in human ovarian tumours. In complementary experiments in tumour cell lines, we will manipulate RTK pathway expression in vitro to assess the influence of growth factor signalling on chemotherapy response.

References:

1. Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer British Journal of Cancer 107, 1327-1336, 2012

2. Rethinking ovarian cancer: recommendations for improving outcomes Nature Reviews Cancer 11, 719-725, 2011

3. The biology of ovarian cancer: new opportunities for translation Nature Reviews Cancer 9, 415-428, 2009

4. Beyond chemotherapy: targeted therapies in ovarian cancer Nature Reviews Cancer 9, 167-181, 2009

Other requirements:

Minimum of 2:1 degree in biological sciences or equivalent, IELTS English Language score of 6.5 overall (no component less than 6.0)

 

Supervisor: 
Dr Gillian Smith
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Stipend level (if applicable): 

N/A