Eicosapentaenoic acid: Optimising anti-colorectal cancer omega-3 fatty acid therapy through better understanding of mechanisms of action and cellular resistance.

SCHOOL OF MEDICINE

Eicosapentaenoic acid (EPA) is an omega-3 fatty acid found in fish oil supplements and oily fish. There is substantial pre-clinical evidence that EPA has significant anti-colorectal cancer (CRC) activity. We were the first team to show that EPA reduced tumour number and size in a randomised clinical trial (1).
In order to investigate the mechanism underlying the anti-CRC activity of EPA, we have established two syngeneic mouse CRC tumour models (2) and isogenic CRC cell lines with varying sensitivity to EPA. Using these CRC cell models, we performed two complementary whole genome expression microarrays in order to identify genes that may have a role in mediating cancer cell response and/or resistance to EPA. Several exciting novel gene targets with potential as a new anti-cancer target have emerged from these screens, including an orphan G-protein coupled receptor, details of which cannot be disclosed here for intellectual property reasons.
The aim of this PhD project is to investigate the expression and function of one or more of these candidate genes in modifying the response to EPA or as an anti-cancer target in its own right. The student will examine the effect of siRNA ‘knockdown’ and over-expression of each candidate gene on EPA sensitivity and viability of our established cell lines, which will confirm the functional relevance of one or more targets. The student will then perform a comprehensive series of expression studies in human CRC cell lines and banked human CRC tissue from our clinical trials for the most promising of the screen target genes, using the full range of molecular and cellular biology techniques. The student will then develop a suitable stable cell line model in order to build further the scientific case for detailed pharmacological work-up of the gene target. The candidate will also test whether one or more gene targets can be used as a predictive biomarker of response to EPA by studying gene expression in clinical samples obtained from our on-going clinical trials (3), thus ‘personalising’ EPA therapy.
The successful candidate will join a multidisciplinary team of research fellows, research assistant and PhD/MD students with expertise ranging from cancer pharmacology and cell biology to molecular imaging and nanotechnology.