Award Title: OPTIMISTICC: OPportunity To Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer
Funder: Cancer Research UK

Abstract: Background  Our Grand Challenge team investigators have discovered that bowel cancers and pre-cancerous states of the bowel are associated with distinct microbiota, including enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, and Fusobacterium nucleatum. Furthermore, we have pre-clinical evidence that treating bowel pre-cancers and cancers with anti-microbial agents can limit tumour growth.  Aims  Our research programme aims to understand how the microbiome contributes to the development and progression of bowel cancers, and to use this understanding to improve diagnosis and treatment.  Our objectives are to: 1) Map the colorectal cancer microbiome. 2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. 3) Share our data, methods, and concepts with the broader scientific, medical, and patient communities.  Methods  1) Map the colorectal cancer microbiome. a. Bowel cancer risk: We will perform microbiome sequence analysis of stool samples and bowel tissues from 2000 individuals at risk for hereditary bowel cancer and 15,000 individuals at risk for sporadic bowel cancer, and will look for an association between the microbiome and cancer development. b. Epidemiology of bowel cancer: We will investigate a cohort of 10,000 colorectal cancers for microbiome characteristics and their relationship to geography, lifestyle, and tumour location. c. Bacterial localisation within tumours: We will use single-cell RNA sequencing and microscopic analyses to determine the composition, localisation and cellular associations of the microbiota within tumour tissue.  2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. a. Modelling the impact of microbiota on cancer models: We will reconstitute the microbiota and immune cell components in organoid and mouse models of bowel cancer and measure their impact on tumour growth and behaviour. b. Patient response to treatment: We will investigate the association of the microbiota with patient response to therapies. c. A clinical trial of a novel therapeutic: We will perform the first clinical trial of a microbial community replacement agent in colorectal cancer. d. Development of novel therapeutics: We will investigate the pre-clinical development of anti-microbial approaches including vaccination, targeted antibiotics, and predatory bacteria.  3) Share our data, methods, and concepts with the broader scientific, medical, & patient communities.  How the results of this research will be used  Our research will test the hypothesis that the bowel cancer microbiota is tumour-promoting and assess methods to treat bowel cancer by microbiome modulation. We expect that this work will be used to improve and develop methods for bowel cancer treatment and control.

Lay Abstract: Background  Our Grand Challenge team investigators have discovered that bowel cancers and pre-cancerous states of the bowel are associated with distinct microbiota, including enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, and Fusobacterium nucleatum. Furthermore, we have pre-clinical evidence that treating bowel pre-cancers and cancers with anti-microbial agents can limit tumour growth.  Aims  Our research programme aims to understand how the microbiome contributes to the development and progression of bowel cancers, and to use this understanding to improve diagnosis and treatment.  Our objectives are to: 1) Map the colorectal cancer microbiome. 2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. 3) Share our data, methods, and concepts with the broader scientific, medical, and patient communities.  Methods  1) Map the colorectal cancer microbiome. a. Bowel cancer risk: We will perform microbiome sequence analysis of stool samples and bowel tissues from 2000 individuals at risk for hereditary bowel cancer and 15,000 individuals at risk for sporadic bowel cancer, and will look for an association between the microbiome and cancer development. b. Epidemiology of bowel cancer: We will investigate a cohort of 10,000 colorectal cancers for microbiome characteristics and their relationship to geography, lifestyle, and tumour location. c. Bacterial localisation within tumours: We will use single-cell RNA sequencing and microscopic analyses to determine the composition, localisation and cellular associations of the microbiota within tumour tissue.  2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. a. Modelling the impact of microbiota on cancer models: We will reconstitute the microbiota and immune cell components in organoid and mouse models of bowel cancer and measure their impact on tumour growth and behaviour. b. Patient response to treatment: We will investigate the association of the microbiota with patient response to therapies. c. A clinical trial of a novel therapeutic: We will perform the first clinical trial of a microbial community replacement agent in colorectal cancer. d. Development of novel therapeutics: We will investigate the pre-clinical development of anti-microbial approaches including vaccination, targeted antibiotics, and predatory bacteria.  3) Share our data, methods, and concepts with the broader scientific, medical, & patient communities.  How the results of this research will be used  Our research will test the hypothesis that the bowel cancer microbiota is tumour-promoting and assess methods to treat bowel cancer by microbiome modulation. We expect that this work will be used to improve and develop methods for bowel cancer treatment and control.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS