The role of the immune micro-environment in the evolution of colitis-associated cancer

Medical Context:

Around 1 in 500 people in the United Kingdom suffer from inflammatory bowel disease (IBD), a set of disorders that includes both Crohn's disease and Ulcerative Colitis (UC), and the incidence is rising. Bowel cancer is the most feared complication of IBD; these patients develop more aggressive cancer tumours at a younger age than the general population. These patients are therefore enrolled in a regular colonoscopy surveillance programme to detect pre-cancerous changes (called dysplasia) and early cancer. St. Mark's hospital, one of my host institutions, conducts the world's oldest, and one of the largest, surveillance programmes in the world. Analysis of their programme registry reveals that patients with UC affecting their whole colon have a lifetime cancer risk of 20%.

Nevertheless, cancer surveillance in IBD faces several critical challenges. Despite advances in technology, dysplasia remains difficult to detect. The majority of patients with IBD do not get bowel cancer, meaning that for many patients these expensive procedures are uncomfortable and unnecessary. Even when pre-cancerous dysplasia is detected, the most appropriate management plan is uncertain. We have shown that the ten-year cancer risk from early dysplasia is only 30%; even in advanced dysplasia that risk is only 50%. Some patients opt for more intensive endoscopic surveillance, while accepting the higher risk of bowel cancer. Others undergo surgery to remove their whole colon, with all the associated risks of a major operation and consequences of life with a stoma. As a gastroenterologist and endoscopist who contributes to the St. Marks IBD surveillance programme, I am all too aware that these challenges reflect how little we know about the biological pathways and timelines leading to bowel cancer in IBD.


Scientific Context:

My host laboratory at the Barts Cancer Institute has demonstrated that mutations accumulate in the lining of the IBD bowel years before the development of cancer, and that stem cells lining the bowel are key to the spread of mutations. We suspect that changes in the environment surrounding bowel stem cells may in fact be the driving force behind the development of cancer.


Research Plan:

This PhD project will combine the unparalleled clinical resources of St. Mark's Hospital, with the scientific expertise of the Barts Cancer Institute, who have an established record in studying bowel cancer evolution. The latest molecular and genetic analysis techniques will be used to analyse fresh and archived tissue derived from 100 IBD surveillance endoscopies in patients with bowel cancer, and compare the mutation burden, inflammatory activity and stem cell behaviour to samples from 300 similar patients who are cancer free.


Research Aims:

1- Ultimately, this research effort will address the important issue of predicting cancer risk: we will develop a laboratory test that can determine if a patient with IBD is likely to develop cancer within the next few years. If successful, this study will improve the quality of life of patients with IBD by increasing focus on those high risk patients, while simultaneously providing significant cost savings to the NHS by sparing many low risk patients from frequent unnecessary invasive colonoscopies and/or surgery.

2- Our basic scientific understanding of IBD-related bowel cancer remains strikingly deficient compared to other typed of CRC. This project will contribute greatly towards filling those gaps.

3- My findings will have implications for researches in bowel cancer at large. The novelty of this proposed PhD project relates to the fact that this will be the first study to simultaneously measure genetic, immunological and stem cell changes over time to determine how bowel cancer develops, and can be replicated in other pre-cancerous conditions.

Background: Patients with ulcerative colitis (UC) have a significantly increased risk of developing colorectal cancer (CRC), and so are entered into endoscopic surveillance programmes with the aim of detecting pre-cancerous dysplastic lesions. The detection and clinical management of these lesions remain challenging, leading to over-diagnosis and over-treatment of CRC risk.

Hypothesis: We have demonstrated that epithelial clonal evolution underpins UC-mediated carcinogenesis; however, this evolution must be critically dependent on the micro-environmental context. We hypothesise that the stromal microenvironment in UC patients co-evolves alongside epithelial mutation accumulation in the colitis-dysplasia-carcinoma sequence, and that these micro-environmental changes represent a powerful biomarker of cancer risk.

Key Goals: The particular scientific novelty of this proposed project is my ability to study the co-evolution of epithelial clonal populations and stromal microenvironment composition in the UC colon. By combining the unparalleled clinical resources of the world's oldest (and the UK's largest) IBD surveillance programme at St. Mark's Hospital with the scientific expertise of Barts Cancer Institute, I aim to:

1- analyse the micro-environmental composition in archival samples from 100 patients who progress to cancer (progressors) and 300 matched non-progressors.

2- correlate the micro-environmental composition in these samples with the pattern of epithelial somatic mutations.

3- use RNA-seq on fresh samples derived from a subset of progressors and non-progressors to characterise genome-wide the paired micro-environmental and epithelial cell biology, and assess the impact on stem cell biology during progression.

Ultimately, I aim use my micro-environmental characterisation to develop a biomarker of CRC risk that spares low risk patients from unnecessary colonoscopy and surgery, and validate its utility in a future prospective clinical study.

1- Patients with inflammatory bowel disease:

Analysis of the St. Mark's IBD surveillance group demonstrates that the 40-year risk of bowel cancer risk for patients with extensive ulcerative colitis stands at 20%. While this risk is much higher than in the general population, it means that the majority of patients with IBD will never develop bowel cancer. At present, every patient with longstanding extensive colonic IBD will undergo repeated colonoscopies approximately every 3 years. The laxative-based bowel preparation prior to colonoscopy is unpleasant, and the surveillance colonoscopies themselves are not only invasive, uncomfortable and inconvenient for patients, but also carry a risk of complications including perforation.

The current surveillance program faces further limitations: namely that dysplastic lesions in IBD are often flat and therefore easily missed at endoscopy, and that histological grading of dysplasia suffers from high inter-observer variability. The majority of patients with UC dysplastic lesions do not develop cancer, and many cancer patients do not have a preceding dysplasia diagnosis. As a result, current clinical practice leads to over-diagnosis and over-treatment for patients opting for surgery when dysplasia is detected, and uncertainty as to the frequency and duration of intensive surveillance for those opting for active monitoring. With dysplasia now detected in up to 10% of surveillance colonoscopies, accurate cancer risk stratification in UC is a major unmet clinical need.

Ultimately, I aim use my micro-environmental characterisation to develop a biomarker of CRC risk that spares low risk patients from unnecessary colonoscopy and surgery, and validate its utility in a future prospective clinical study.



2- Gastroenterology Societies and other relevant guideline-generating organisations:

Surveillance colonoscopies are now recommended by the British Society of Gastroenterology (BSG) and other gastroenterology societies (e.g. European Crohn's & Colitis Organisation, American Gastroenterology Association). However, there is a lack of consensus between these organisations as to the most appropriate frequency of endoscopic surveillance. St. Mark's Hospital runs the world's oldest IBD cancer surveillance programme, and remains by far the country's largest programme. Many of the current guideline authors are based in his hospital, and the current regimen (e.g. the recent adoption of chromoendoscopy) has been derived from studies based on the St. Mark's cohort. It is therefore likely that any prospectively validated biomarkers will be considered during guideline updates.



3- IBD clinicians and endoscopists:

Due to the lack of evidence in this field, clinicians operating in this field struggle on how best to advise patients with dysplasia or other high risk clinical features. Validated cancer risk biomarkers will provide more clarity for these difficult patient consultations.



4- In the long term, healthcare service providers including the National Health Service:

The current surveillance protocol recommended by the BSG has been deemed cost-effective by NICE, and as such is implemented nationwide. However, this programme carries a significant financial cost to the NHS at £17,500/quality-adjusted life year. The absolute cost is likely to increase with the rising incidence of inflammatory bowel disease, in combination with an ageing population. Recent advances in medical therapy may also mean that increasing numbers of patients with severe inflammation have avoided surgery and retained their bowels. Any validated cancer risk biomarker has the potential to result in significant cost savings.



5- Industry:

While there are no immediate commercial applications from this project, any generated biomarkers may hold commercial value. Subject to Intellectual Property restrictions by the university, I would be well placed to promote any generated biomarkers to industry.