Colorectal adenoma recurrence: harnessing lifestyle and metabolic biomarkers to increase precision for risk stratification and cancer prevention

Supervisors:
Prof Karen Brown and Dr Tom Yates

Application Deadline:
Noon on 17th February 2017

Background:
Therapeutic cancer prevention (also known as chemoprevention) is increasingly seen as a cost-effective approach to reducing cancer incidence and mortality. However, to successfully translate and implement effective therapies it is essential to improve the identification of individuals at high-risk of developing cancer. Patients presenting with colorectal polyps, a precursor to cancer, represent an ideal population for evaluating, and ultimately using, therapies in a secondary prevention setting. After polyp resection, patients remain at elevated risk for recurrence and/or cancer development, with the degree largely dependent on polyp number and size. However, the majority of patients do not recur. Therefore, further defining risk for this population would enable interventions to be targeted to those most likely to experience a net benefit and avoid over-treatment. Obesity, physical inactivity, diet, diabetes and metabolic syndrome1 have repeatedly been associated with risk of several cancers, including colorectal, and excess bodyweight has been linked to the presence of adenomas2. However, underlying mechanisms have not been established and there is scope to greatly improve markers of risk through more comprehensive metabolic characterisation.

Additionally, we have shown that a high-fat diet promotes colorectal tumourigenesis in mouse models and influences whether preventive interventions such as resveratrol and aspirin work. These agents exert activity both locally in colorectal tissue and systemically via reversal of fat-induced changes in plasma lipid profiles3. Our findings suggest these agents may be more effective in people with metabolic dysregulation and/or consuming a high-fat diet. Consequently, characterisation of metabolic and lifestyle factors in patients with colorectal polyps will be vital for tailoring specific preventive therapies to individuals.

Aim:
The aim of this project is to conduct metabolic phenotyping to identify individuals at high-risk for colorectal adenoma recurrence and reveal new mechanistic insight and/or biomarkers for monitoring the efficacy of therapies in prevention trials.

We hypothesize that comprehensive lifestyle and metabolic phenotyping (including harnessing metabolomics/proteomics analysis), can be employed to increase precision for identifying individuals at high-risk of colorectal adenoma recurrence and reveal mechanisms underlying the association.

Environment:
This is a highly translational project encompassing a multi-disciplinary programme of research with the student imbedded within both the Chemoprevention Group, Department of Cancer Studies and Diabetes Research Centre. The student will split their time between the groups and benefit from collaborative interactions with two complementary research teams.

Research Plan:
The student will help with the recruitment of patients identified through the bowel cancer screening programme (BCSP) as having had high or intermediate risk polyps removed. They will then conduct broad ranging metabolic phenotyping of the patients using both targeted assays for established markers of metabolic health (such as HbA1c, cholesterol, fasting insulin and glucose, leptin, adiponectin) and state of the art metabolomics/proteomics LC-MS/MS methodology for biomarker discovery. The ‘omics analysis will be conducted in collaboration with Dr Jones (Cancer Studies) and Prof Suzuki (Cardiovascular Science). Information on lifestyle and dietary behaviours will also be collected using gold standard measures. The student will compare these parameters between patients that recur/progress during standard screening intervals and those that don’t, to identify panels of risk biomarkers.

Impact and outcomes:
Results from this project will improve the identification of patients for inclusion in therapeutic prevention trials on the basis of both elevated risk and having metabolic dysfunction amenable to correction by certain agents. Findings could also impact on adenoma/cancer surveillance practices. The findings will feed into a planned polyp prevention trial currently under development, ensuring the work will lead to immediate impact in patients.