The effects of randomised dietary, physical activity and metformin

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The effects of randomised dietary, physical activity and metformin
Title of Project: The effects of randomised dietary, physical activity and metformin interventions on the serum
metabolome and DNA methylome of men at risk of, or with, localised or advanced prostate cancer
Supervisors: Dr Athene Lane, Professor Richard Martin & Dr Lucy Hackshaw-McGeagh.
Contact: [email protected]
Overall aims: To investigate the effect of randomised dietary, physical activity or metformin therapy interventions
on the metabolome and DNA methylome of men at risk of, or with, localised and advanced prostate cancer.
Background: Physical activity, lycopene, green tea, plant-based diets and metformin (a drug used in the
treatment of type 2 diabetes) have been associated with reduced risk of both prostate cancer development and
its progression to fatal disease.(1) However, the mechanisms are still to be fully elucidated.(1) One hallmark of
cancer(2) is that they adapt to their metabolic environment to satisfy the increased energy and biosynthetic needs
of proliferating cells. This suggests that variations in the circulating metabolome (small molecule metabolites that
are involved in metabolism) could influence cancer development or progression.(3) Epigenetic regulation of gene
expression by DNA methylation is a second hallmark of cancer. DNA methylation signatures provide biomarkers of
historical exposures and cause cancer through the inactivation of tumour-suppressor genes.(4)
Hypotheses: The student will test the hypotheses that physical activity, lycopene, green tea, plant-based diets or
metformin are causally associated with metabolomic or DNA methylation variation and that these changes are in
turn linked to prostate cancer development or its progression to fatal disease.
Specific research questions:
1. What are the effects of dietary (lycopene or green tea or plant-based diet), physical activity or metformin
therapy interventions on the metabolome and DNA methylome of men at risk of, or with, localised and
advanced prostate cancer? This will provide insights into the potential mechanisms of action of these
experimental interventions on downstream metabolic pathways.
2. Are small molecule metabolites and DNA methylation sites that are altered by these experimental
interventions causally related to the risk or progression of prostate cancer. This could identify potential
metabolic targets that could be intervened on to prevent prostate cancer risk or progression.
Methods: The student will analyse three randomised controlled trials (RCTs) (ProDiet,(5) PrEvENT(6) and a new
metformin/physical activity trial) and a large prostate cancer consortium of case-control studies (PRACTICAL,
45,000 cases and 28,000 controls(7)). ProDiet is an RCT of dietary interventions (n=133) in men at increased risk
of prostate cancer who were randomly allocated to lycopene (lycopene or placebo or lycopene rich diet) and
green tea (green tea or placebo or green tea drink) for 6months.(5) PrEvENT is an RCT of interventions that
modify nutrition and physical activity over a 6 months follow-up period in men with localised prostate cancer
(N=108).3 A new RCT is being established that will randomly allocate men with advanced prostate cancer to
physical activity and metformin interventions over 6 months follow-up. The student will have an opportunity to
be involved in the co-ordination of this new trial, gaining valuable experience of fieldwork. Within these trials,
over 220 serum metabolites will be measured using NMR spectroscopy, and epigenome wide association studies
conducted by the student, on blood samples taken at enrolment and 6 months after randomisation. The student
will then use a technique called Mendelian randomization(8) to estimate the causal effects of metabolites altered
by the interventions on prostate cancer risk and survival, using genetic data in the PRACTICAL consortium. High
level training in RCTs, statistical analysis, genetics, epigenetics and metabolomics will be provided. .
References
1. World Cancer Research Fund International/American Institute for Cancer Research Continous Update Project Report: Diet, Nutrition, Physical Activity,
and Breast Cancer Survivors. 2014. Available at: www.wcrf.org/sites/default/files/Breast-Cancer-Survivors-2014-Report.pdf.
2. Hanahan D, Weinberg Robert A. Hallmarks of Cancer: The Next Generation. Cell;144:646-674.
3. Morin A, Letouze E, Gimenez-Roqueplo AP, Favier J. Oncometabolites-driven tumorigenesis. Int J Cancer. 2014;135:2237-2248.
4. Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17.
5. Horwood J, Avery K, Metcalfe C, et al. Men's knowledge and attitudes towards dietary prevention of prostate cancer. BMC Cancer. 2014;14:812.
6. Hackshaw-Mcgeagh L, Lane JA, Persad R, et al. Prostate Cancer evidence of exercise and nutrition trial (PrEvENT). Trials. 2016;17.
7. Davies N, Gaunt T, Lewis S,et al. The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848
cases and 20,214 controls from the PRACTICAL consortium. Cancer Causes & Control. 2015;26:1603-1616.
8. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics.
2014;23:R89-R98.

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