Does aspirin increase the clinical response to pre-operative chemo-radiotherapy [CRT] in rectal cancer?

Bowel cancer remains the second most common cause of cancer deaths in the UK, highlighting an urgent need to improve the efficacy of current therapies. The aim of this project is to investigate whether taking aspirin can make conventional therapies more effective and therefore significantly improve the life-expectancy of people with bowel cancer.

Although evidence for the role of aspirin in the prevention of bowel cancer is mounting, its use in combination with established therapies has so far been largely overlooked. Important work from our laboratory has shown that aspirin can potentially kill cells which fuel the growth of tumours (commonly referred to as cancer initiating cells or cancer stem cells). It is these cells that are thought to be resistant to conventional therapies like radiotherapy and are also responsible for the regrowth of the tumour after treatment has finished. This has led to the exciting possibility that using aspirin in conjunction with conventional treatments such as radiotherapy, may improve the ability of the therapies to target the cancer stem cells, and hence increase the effectiveness of conventional treatments. Importantly in the treatment of rectal cancer (a type of bowel cancer) combined chemotherapy and radiotherapy are used to shrink the cancer before surgery. However for a significant number of patients there will be little or no response, meaning that this subgroup of patients are treated unnecessarily, and their surgery delayed for no benefit. We propose that in combination with conventional therapies, aspirin will increase the tumour response to chemo-radiotherapy (CRT) by targeting the cancer initiating cell population. This work has led to the ASPIRE (ASPirin and Irradiation in REctal cancer) clinical study, which aims to determine whether regular aspirin use can increase the shrinkage of rectal cancers after CRT. The aim of the current study is to investigate the mechanism by which aspirin can target the cancer stem cell-like population and identify markers that will inform which rectal cancer patients are most likely to benefit from pre-operative CRT.

Method(s) used: Studies in colorectal cancer cell lines will be used to determine the mechanism by which non-steroidal anti-inflammatory drugs [NSAIDS] (including aspirin) can sensitise bowel cancer cells to irradiation. Findings from the laboratory based study will be validated in patient samples available from the ASPIRE cohort study. In the ASPIRE trial, patients are put into three groups: i) those taking aspirin; ii) those taking other NSAIDS; iii) those taking neither NSAIDS nor Aspirin. Patients are then monitored from diagnosis, throughout their treatment (routine NHS pre-operative CRT) until surgery. Tissue, blood and urine samples are collected to investigate the mechanism involved in tumour response to conventional CRT, and to develop new biomarkers (markers that allow us to predict the likelihood that the treatment will be effective).

Outcome: It is anticipated that this study will identify novel clinical uses for aspirin, improving the success of conventional treatments for bowel cancer. We aim to find markers that identify those patients who will benefit most from pre-operative CRT, meaning that those patients who will not respond can be spared the unnecessary CRT and go straight to surgery.

Colorectal cancer remains the second most common cause of cancer-related death in the UK. Although the success of surgical resection of rectal tumours has improved significantly with the use of pre-operative chemo-radiotherapy (CRT), the reason why some patients respond better to CRT than others remains unknown. There is an urgent need, not only to develop new treatments, but also to find ways to improve the response to existing therapies.

Although evidence for the use of aspirin in colorectal cancer prevention is mounting, its use as an adjuvant to established therapies has been largely overlooked. We recently discovered that aspirin can inhibit the BCL-3 pro-survival factor, and suggest this may contribute to its chemopreventive action. In understanding the action of non-steroidal anti-inflammatory drugs (NSAIDs), the aim of these experiments is to demonstrate the importance of targeting BCL-3 function as well as COX/PGE2 for sensitizing cells to irradiation.

Combining mechanistic studies in human colorectal cancer cell lines with results from an ongoing clinical cohort study, we will investigate whether NSAIDs that inhibit both COX/PGE2 and BCL-3 signalling pathways are more effective than COX-2 selective inhibitors in sensitising cells to gamma-irradiation. The role of BCL-3/beta-catenin signalling in promoting a cancer stem cell related (SCR) phenotype, and the impact of SCR protein expression on radiation sensitivity will be investigated. Results from the in-vitro study will be validated in samples from rectal cancer patients undergoing pre-operative CRT.

This work aims to establish a novel use for NSAIDS as therapeutic adjuvants, increasing the tumour response to conventional therapy. In understanding the mechanism of action we will identify novel biomarkers that can be used to predict those patients that will most benefit from pre-operative radiotherapy.

This project will aim to determine the role of the COX-2/PGE2 and NFKB/BCL-3 pathways in resistance of rectal cancers to neo-adjuvant irradiation using in-vitro and in-vivo mechanistic methodology. It will also aim to understand the role that aspirin plays in sensitising rectal cancers (via the pathways mentioned) to this therapy. Its primary impact will be to people who have the disease, the healthcare teams that treat people with rectal cancer and scientists or clinicians who are currently undertaking research on rectal cancer, including my personal development.

The research will improve care for patients by ensuring that only those who will respond to neo-adjuvant radiotherapy receive it, thereby reducing the burden of side-effects. I also aim to improve the efficacy of neo-adjuvant radiotherapy and in the long term investigate to see if this has a beneficial impact on patients' disease-free survival. These impacts will also serve to lessen the cost to the NHS of rectal cancer management through offering personalised medicine that is more efficacious. Critically the research will serve to narrow the gap between laboratory and NHS by influencing the design of future randomised controlled trials which will be of significant interest to both the surgical and scientific communities. I aim to inform patients and the public about my research with a multifaceted program including newsletters, social media and interaction with the public at open days and other events. Also I will provide a forum for our patients and participants to provide their opinions through an advisory group, which we will use to design future research.

My research will be published in high impact, peer-reviewed journals to enable dissemination to clinical and scientific communities. I will also submit abstracts to major surgical and scientific conferences with the aim of presenting at these conferences to further promote the importance of my work.

If successful this preliminary work will lead onto larger randomised controlled trials. It is likely that following successful clinical trials organisations such as the National institute for Health and Care Excellence (NICE) will use these data to update and improve existing guidance on the management of rectal cancer. Other organisations to benefit will be the UK Therapeutic Cancer Prevention Network (UK-TCPN) who would be able to use my results to inform their policy on the future design of trials regarding preventative drugs.

There will be significant impact to my career and personal skill set from completing my PhD at a world-renowned university, with a research group that has a exemplary track record of training both scientists and clinicians. Therefore the impact of this research will not only be seen in the short-term but also throughout the rest of my career. Training will be achieved through regular contact from my supervisors and completion of courses both at the Bristol Doctoral College and externally at institutions such as the Royal Society. The experience gained by previous clinicians, who completed research training in this laboratory, has directly contributed to further progression of their careers. For example one is now in a substantive NHS Consultant position and is contributing to ongoing research including becoming the Principal Investigator in their NHS Trusts for the ongoing ASPIRE trial run by this laboratory. I anticipate that with this MRC training fellowship I will be able to apply and obtain competitive consultant surgical posts in research ready organisations, which will enable a career as a clinician scientist.

Please see the attached 'Pathways to Impact' document to review full details of my proposed impact.