Modulating the role of prostaglandins in colorectal cancer stem cells survival

Chief Investigator	Dates	Funding Stream	Amount
Mr Michael Thomas	01/04/2014 -31/10/2014	Above and Beyond Spring 2013	£19,375
Co-Investigators
Ms Kat Baker (née Gash)	UHB Colorectal ST8 Registrar
Mr Adam Chambers	UHB Clinical Lecturer in Colorectal Surgery

 

Summary

Bowel cancer is the second most common cause of cancer deaths in the UK. 40% of patients with advanced disease are resistant to treatment. Cells within cancers, known as cancer stem cells [CSC] drive tumour growth. These cells are resistant to conventional therapies and even if a patient has a good initial response to treatment, the resistant CSCs can cause the cancer to re-grow. This research investigates exciting new evidence that drugs such as aspirin [NSAIDs] can sensitize CSCs to chemo-radiotherapy. This work will lead to new ways of using NSAIDs clinically, to improve conventional treatments and patient survival.

Work carried out

Laboratory Study:

• We have completed a series of in vitro experiments demonstrating that Aspirin reduces cell yield and increases apoptosis (cell death) in colorectal carcinoma and adenoma cell lines.

By using a laboratory irradiator to replicate the radiotherapy that patients receive, we have shown that when colorectal cancer cells are treated with Aspirin prior to radiation,there is a two-fold increase in cancer cell death, (compared to cells irradiated without Aspirin). 

• Most colorectal cancers have elevated levels of prostaglandin, which enhances the activity of two pathways (LGR5 and BCL-3), which promote colorectal cancer stem cell function and survival.  NSAIDS (such as aspirin) work by reducing prostaglandin levels.

Through a series of experiments with colorectal cancer cells, we have demonstrated that treatment with Aspirin reduces activity in these pathways (LGR5 and BCL-3) and reduces cancer cell survival. 

This is compelling evidence supporting the notion that Aspirin has an efficacious role in colorectal cancer treatment.

Clinical Study:

• To translate this clinically we established a multi-centre prospective NIHR portfolio adopted cohort study at six NHS sites, (ASPIRE: ASPirin & Irradiation in REctal cancer), analysing tumour tissue from patients with rectal cancer and investigating the impact of taking aspirin or NSAIDs during chemo-radiotherapy on tumour response.
• We successfully recruited 93 patients with rectal cancer (from a target of 80) and we are currently studying various markers in participant's blood, urine and tumour specimens, to further investigate Aspirin's role as a novel adjunct.
• This exciting work may further justify the use of aspirin as a novel treatment adjunct in colorectal cancer and has huge potential to improve treatment response, having an immeasurable positive impact on cancer patients and their families.

Main findings

We have demonstrated in the laboratory that treating colorectal cancer cells with Aspirin prior to irradiation leads to a two-fold increase in cancer cell death. This results in increased sensitivity to radiation in the cancer cells.

We established a clinical study (ASPIRE: ASPirin & Irradiation in REctal cancer), which was led by UHBristol and carried out at 5 other hospital trusts, to investigate whether these laboratory findings are replicated in patients. 93 patients were recruited, and tumour, blood and urine samples collected. Work is ongoing to analyse these samples.

Impact

This exciting work suggests that Aspirin may have a novel role as an adjunct to treatment for colorectal cancer. In the future, Aspirin may be used clinically to provide targeted therapy to patients, improving colorectal tumour response to chemo-radiotherapy, and potentially increasing patient survival. This work has also directly led to further successful funding applications to carry out additional research into the mechanisms by which aspirin impacts the response to chemoradiotherapy in rectal cancer.

Further funding applications

David Telling Charitable Trust research grant, £25,000, Miss Kat Gash and Mr Michael Thomas 2014

Bowel Cancer UK grant, £24,696 Alex Greenhough, Mr Adam Chambers, Prof Ann Williams

Application in progress:

Funding for analysis of blood samples from ASPIRE is currently being sought, Mr Adam Chambers 2019.

Project outputs

 

Other project outcomes

This work has been in full collaboration with the Cancer Research UK Colorectal Tumour Biology Group at The University of Bristol, School of Cellular and Molecular Medicine. The clinical aspect of this work (ASPIRE study) has led to the collaboration of 6 hospital sites:

• UHBristol
• North Bristol NHS Trust
• Cheltenham General Hospital
• Royal Devon & Exeter NHS Foundation Trust
• Royal United Hospital Bath
• Abertawe Bro Morgannwg University Health Board