Professor Mark Hull EPA & colorectal cancer trial update


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EPA has shown positive benefits for colorectal cancer. Treatment with EPA (2g daily for 6 months) on rectal polyp growth resulted in a 22.4% decrease in adenoma numbers and a 29.8% reduction in adenoma size.

We were delighted to host Professor Mark Hull this summer as he delivered an exciting webinar on his journey through colorectal cancer research and the current World Cancer Research fund trials he is leading. These studies are investigating the use of EPA (using our Pharmepa RESTORE supplement) for the prevention and treatment of bowel cancer and metastatic liver cancer. Dr Nina Bailey hosted the webinar and now revisits summarises what you need to know about the role of EPA in bowel cancer and the trials underway.

Colorectal cancer

Bowel cancer (colorectal cancer or CRC) is one of the most common forms of cancer in the UK. Most forms of CRC develop slowly over several years, starting with small non-cancerous growths – known as polyps – that protrude from the inner lining of the colon or rectum. Not all polyps turn into cancer, and around 80% of cases of potential CRC are actually preventable when caught early. For people whose CRC is detected at an early stage, the five-year survival rate is now higher than 90%. The standard treatment for early CRC, and CRC prevention is to identify and remove bowel polyps, which reduce future bowel cancer risk, but this is not 100% effective. The use of drugs or nutritional supplements as anti-cancer agents (chemoprevention) is an attractive strategy for prevention of bowel cancer, in combination with standard screening methods, particularly if the chemoprevention agent used is safe, well tolerated and cost effective. Numerous agents have been identified as potentially chemo preventative, including several pharmacotherapies such as aspirin, ibuprofen and statins, and nutrients such as omega-3 fatty acids and folate. Due to very promising findings to date, ongoing clinical trials using the omega-3 fatty acid EPA for primary prevention of bowel cancer, and the prevention of metastatic disease, are currently underway and early outcomes are extremely encouraging.

Diet, EPA and CRC in context

Chronic inflammation (driven by a high AA to EPA ratio) is known to be a key driver of CRC and the risk of developing CRC is significantly increased in those individuals suffering with pre-existing inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease. The ratio of AA to EPA within the colic mucosa has the potential to modify the inflammatory process. Inflammation creates the ideal “tumour microenvironment” acting as an enabling factor in cancer onset and progression, by encouraging increased cell proliferation, cell survival, cell migration and angiogenesis within the tumour site. Modifying the diet to reduce systemic inflammation by manipulating the AA to EPA ratio has the potential to modify CRC risk, with high strength pure EPA currently believed to be the most effective management tool for restoring inflammatory balance.

EPA mechanisms in colorectal cancer

Experimental and clinical data have shown that EPA possesses a number of cancer specific beneficial effects including reduced tumour growth, suppression of angiogenesis and inhibition of metastasis. The involvement of cyclooxygenase (COX) enzymes in the early development of CRC has seen a significant interest in the possible effects of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and selective cyclooxygenase-2 (COX-2) inhibitors, as interventions for protecting against CRC development. Cyclooxygenase-derived prostaglandin E2 is a proinflammatory lipid mediator known to promote tumour progression.[1]  In animal colorectal cancer models, omega-3 fatty acids protect against colorectal cancer by inhibiting COX, which suppresses eicosanoid biosynthesis from AA, thereby inhibiting production of proinflammatory and tumourigenic prostaglandins and leukotrienes.

Current EPA clinical trials

Because EPA rather than DHA is an effective competitive inhibitor of AA for COX enzymes, increasing colorectal mucosal EPA levels with pure EPA as opposed to raising both EPA and DHA with a blend of the two is more effective for both treatment and prevention. The use of pure EPA, over EPA/DHA blends is supported by studies showing EPA to be significantly more effective than DHA in reducing tumourigenesis in animal models of colorectal cancer, [2] reducing intestinal adenoma multiplicity by 79% in animal models of familial adenomatous polyposis (FAP) [3] and later repeated in human FAP patients. [4] When compared with placebo, the effect of EPA (2g daily for 6 months) on rectal polyp growth in patients with FAP resulted in a 22.4% decrease in adenoma numbers and a 29.8% reduction in adenoma size. [4] The efficacy of EPA as a chemopreventative agent in FAP patients has prompted a larger scale randomised trial of EPA, conducted in patients with a history of colorectal adenoma undergoing colonoscopic surveillance as part of the English Bowel Cancer Screening Programme. Better known as the seAFOod Polyp Prevention Trial, this randomised phase III double blind, placebo-controlled trial, is a 2×2 factorial trial of 2g EPA daily and 300 mg aspirin daily. Participants will be randomly assigned to receive either: placebo + placebo, placebo + EPA, placebo + aspirin or EPA + aspirin; the idea being to deduce whether EPA and aspirin act alone or synergistically to prevent CRC. A synergistic relationship between the two has been proposed and previous research shows that aspirin can irreversibly acetylate the COX enzymes, leading to conversion of EPA to resolvin E1, which has potent anti-inflammatory activity.  This ongoing trial, and collaboration with Igennus as providers of both EPA and placebo, is expected to report initial findings 2016-17. [5]

In addition, pre-clinical evidence of EPA activity against CRC liver metastasis has also been favourable and a phase III, randomised, double-blind, placebo controlled trial, investigating the survival benefits of a daily dose of 2g EPA in patients awaiting surgery for liver metastasis in also about to commence. Known as the EMT2 trail, it will include approximately 450 patients with metastatic CRC and is due to start early 2016, with results due in 2020.

This is very exciting times for EPA research and paves the way for more research, should the results prove beneficial. Professor Hull already has a few questions that will hopefully spark future interest and research. These include: what is the optimal dose and timing of EPA use? Does the use of EPA alone benefit CRC or does the amount of EPA incorporated tissues determine outcomes? Is EPA only important or would EPA plus DHA also be effective? What are the mechanisms of EPA’s anti-cancer actions?

With so many directions that Professor Hull’s work could take, we are excited to be a part of this ground-breaking research and look forward to reporting on the results and new trials that get the go-ahead very soon. So watch this space for research updates and to follow Professor Hull’s work.

References

  1. Wang D, DuBois RN: An inflammatory mediator, prostaglandin E2, in colorectal cancer. Cancer J 2013, 19:502-510.
  2. Petrik MB, McEntee MF, Johnson BT, Obukowicz MG, Whelan J: Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in Apc(Min/+) mice. J Nutr 2000, 130:2434-2443.
  3. Fini L, Piazzi G, Ceccarelli C, Daoud Y, Belluzzi A, Munarini A, Graziani G, Fogliano V, Selgrad M, Garcia M, et al: Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice. Clin Cancer Res 2010, 16:5703-5711.
  4. West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA: Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut 2010, 59:918-925.
  5. Hull MA, Sandell AC, Montgomery AA, Logan RF, Clifford GM, Rees CJ, Loadman PM, Whitham D: A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial. Trials 2013, 14:237.

 

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Personalising omega-3 treatment for optimal results using a biomarker-based approach, by Dr Nina Bailey

Dr Nina Bailey

About Dr Nina Bailey

Nina is a leading expert in marine fatty acids and their role in health and disease. Nina holds a master’s degree in Clinical Nutrition and received her doctorate from Cambridge University. Nina’s main area of interest is the role of essential fatty acids in inflammatory disorders. She is a published scientist and regularly features in national health publications and has featured as a nutrition expert on several leading and regional radio stations including SKY.FM, various BBC stations and London’s Biggest Conversation. Nina regularly holds training workshops and webinars both with the public and health practitioners.