Cancer: Understanding the mechanism(s) of the anti-cancer activity of EPA in order to personalise therapy and improve treatment outcomes

Advanced colorectal cancer (CRC) is the UK’s second most lethal cancer, with limited treatment options for unresectable metastatic tumours. Therefore, novel therapeutic strategies are needed to improve patient outcomes. <br /> Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 polyunsaturated fatty acids (PUFAs), naturally found in cold-water oily fish. Pure EPA is licenced for prophylaxis of cardiovascular events in high-risk individuals and shows promise as an anti-cancer agent to prevent and treat CRC (1). A phase III clinical trial (EMT2) of EPA 4 g daily for prevention of recurrence in treated CRC patients is underway (2). We have recently described a functional insertion-deletion (Indel) polymorphism in the FADS2 gene that predicts prevention of colorectal polyp recurrence by EPA (3). However, the precise mechanism by which the Indel influences cellular sensitivity to EPA and whether Indel genotype is also relevant for DHA treatment is unknown. Understanding the molecular basis of PUFA sensitivity in cell models will help refine the use of FADS2 Indel genotype, and/or other novel markers for best therapeutic use of supplemental or dietary omega-3 PUFAs. <br />

<p>Using cancer and lymphoblast cell models of known Indel genotype, the PhD student will investigate how the Indel polymorphism alters FADS gene expression, transcription factor binding and PUFA synthesis in vitro. There is also the possibility of contributing to clinical genotyping studies and clinical translational work in order to confirm the predictive value of the FADS2 Indel for EPA treatment.</p> <p> </p> <h2><strong>Techniques associated with project:</strong></h2> <p>This project will use a wide range of basic laboratory techniques including cell culture, cell proliferation/apoptosis assays, gene expression studies (at RNA and protein level) and mass spectrometry lipid assays (performed in close collaboration with University of Bradford colleagues). More advanced techniques including ChIP-seq, gene reporter assays and genetic deletion experiments are likely to be needed in order to develop the project further.</p> <p> </p> <h2><strong>References:</strong></h2> <p> </p> <ol> <li>Aldoori J, Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty acids: moving towards precision use for prevention and treatment of colorectal cancer. Gut 2022;71:822-83.</li> <li>Hull MA, Ow PL, Ruddock S, Brend T, Smith AF, Marshall H, Song M, Chan AT, Garrett WS, Yilmaz O, Drew DA, Collinson F, Cockbain AJ, Jones R, Loadman PM, Hall PS, Moriarty C, Cairns DA, Toogood GJ. Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol. BMJ Open 2023;13:e077427.</li> <li>Sun G, Li YN, Davies JR, Block RC, Kothapalli KS, Brenna JT, Hull MA. Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial. Am J Clin Nutr 2024;120:360-368.</li> </ol>

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