Title: Exploiting oncotropic bacteria for early detection of colorectal cancer
Funder: Cancer Research UK

Abstract: Background The earlier a cancer is detected the greater the chance it can be successfully treated. The current faecal occult blood test for colorectal cancer (CRC) has limited accuracy due to the many non-cancer related reasons for faecal blood, e.g. aspirin use. A more accurate test would prevent unnecessary diagnostic endoscopy and reduce waiting times, lead to earlier detection and improved clinical outcomes. We propose to develop a specific test for CRC that uses the safe SL7207 strain of Salmonella typhimurium. SL7207 is an auxotroph that can only colonise CRC and its pre-cursor cells due to the availability of nutrients and immune suppression in the cancer niche. Thus, its presence in the faeces can act as a surrogate marker for CRC. We plan to demonstrate that following administration of SL7207, its persistence in the faeces is indicative of single pre-cancerous colonic polyps, akin to those that present at clinic. Aims: We aim to deliver results that identifies SL7207 as a safe, non-invasive test for human intestinal polyps by meeting the following objectives: 1. Demonstrate that SL7207 can specifically colonise pre-cancerous intestinal polyps. 2. Demonstrate the persistence of faecal SL7207 only in polyp bearing immune-competent animals. 3. Demonstrate the potential of SL7207 to detect and localise human polyps. Methods We will use a combination of genetically engineered and xenograft models of early stage CRC. These models will be treated with our novel reporter strains of SL7207. Using cre-lox technology we will generate single polyps in the mouse colon that represent the two most common types of pre-cancerous polyps, traditional and serrated. These mice will be staged, administered SL7207 and monitored using endoscopy and reporter imaging. Samples will be collected to assess the kinetics of bacterial colonisation and faecal shedding from healthy and tumour bearing animals. The translational capabilities will be demonstrated using immune-deficient mice, capable of eliminating SL7207, to treat human polyp organoids grown orthotopically in the colon. All these mice will be investigated with current equipment at a clinical research facility to demonstrate the potential of novel reporter SL7207 strains for locating tumours How the results of this research will be used. These results will demonstrate the potential of SL7207 for early CRC detection. The data will underpin a CRUK EDX Programme grant application aimed at progressing the technology towards a phase 1 clinical trial and establishing its potential for detecting other tumour types.

Lay abstract: Background The earlier a cancer is detected the greater the chance it can be successfully treated. The current faecal occult blood test for colorectal cancer (CRC) has limited accuracy due to the many non-cancer related reasons for faecal blood, e.g. aspirin use. A more accurate test would prevent unnecessary diagnostic endoscopy and reduce waiting times, lead to earlier detection and improved clinical outcomes. We propose to develop a specific test for CRC that uses the safe SL7207 strain of Salmonella typhimurium. SL7207 is an auxotroph that can only colonise CRC and its pre-cursor cells due to the availability of nutrients and immune suppression in the cancer niche. Thus, its presence in the faeces can act as a surrogate marker for CRC. We plan to demonstrate that following administration of SL7207, its persistence in the faeces is indicative of single pre-cancerous colonic polyps, akin to those that present at clinic. Aims: We aim to deliver results that identifies SL7207 as a safe, non-invasive test for human intestinal polyps by meeting the following objectives: 1. Demonstrate that SL7207 can specifically colonise pre-cancerous intestinal polyps. 2. Demonstrate the persistence of faecal SL7207 only in polyp bearing immune-competent animals. 3. Demonstrate the potential of SL7207 to detect and localise human polyps. Methods We will use a combination of genetically engineered and xenograft models of early stage CRC. These models will be treated with our novel reporter strains of SL7207. Using cre-lox technology we will generate single polyps in the mouse colon that represent the two most common types of pre-cancerous polyps, traditional and serrated. These mice will be staged, administered SL7207 and monitored using endoscopy and reporter imaging. Samples will be collected to assess the kinetics of bacterial colonisation and faecal shedding from healthy and tumour bearing animals. The translational capabilities will be demonstrated using immune-deficient mice, capable of eliminating SL7207, to treat human polyp organoids grown orthotopically in the colon. All these mice will be investigated with current equipment at a clinical research facility to demonstrate the potential of novel reporter SL7207 strains for locating tumours How the results of this research will be used. These results will demonstrate the potential of SL7207 for early CRC detection. The data will underpin a CRUK EDX Programme grant application aimed at progressing the technology towards a phase 1 clinical trial and establishing its potential for detecting other tumour types.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS