Project

Targeting genotoxic pks+ E.coli to prevent CRC development using innovative translational technologies

Code
365S07824
Duration
01 November 2024 → 31 October 2025
Funding
Funding by bilateral agreement (private and foundations)
Research disciplines
  • Medical and health sciences
    • Gastro-enterology
    • Microbiome
    • Cancer therapy
Keywords
Colorectal Cancer E. coli
 
Project description

Colorectal cancer (CRC) is the third most common cancer worldwide, , accounting for approximately 10% of all cancer cases. Approximately half of them will die from the disease, making CRC the second leading cause of cancer-related deaths worldwide. The prognostic five-year survival rate varies from >90 % for patients in early disease stage to about 10% for patients with metastases, emphasizing the importance of early detection of this cancer. Unfortunately, the incidence of colorectal cancer is increasing in the younger population (<50 years old), which are missed in current screening efforts. Consequently, young CRC patients often present with advanced disease upon diagnosis. Increasing evidence indicates that environmental factors linked to a Western lifestyle and diet, strongly contribute to the etiology of CRC, through mechanisms regulated by the intestinal microbiota, the collection of micro-organisms in our gut. The notion that CRC development is mediated by bacterial-host interactions is further supported by the identification of several CRC-promoting bacteria, so called ‘oncobacteria’, including pathogenic E. coli strains. Pks+ E. coli induce DNA damage through the production of a set of enzymes encoded in the polyketide (pks) pathogenicity island, to synthesize the genotoxin colibactin. Colibactin binds adenine residues on opposing DNA strands and cross-links DNA, leading to double stranded breaks and specific mutational profiles4. pks+ E. coli are enriched in patients with inflammatory bowel disease (IBD) and CRC6-8, indicating that pks+ E. coli have a tropism for the inflamed and neoplastic mucosa, and suggesting that pks+ E. coli  may drive a critical positive feedback mechanisms in CRC.

During my PhD research, I have unraveled the mechanisms by which pks+ E. coli drive CRC development, through adhesin-mediated epithelial binding. I identified the critical adhesins FimH and FmlH as crucial mediators of epithelial binding, which allows production of the genotoxin colibactin in close proximity to host DNA, favoring mutagenesis and CRC development. We also discovered that both FimH and FmlH adhesins are essential for effective epithelial binding and CRC development, indicating that pharmacological targeting of either of these adhesins is an effective strategy to prevent pks+ E. coli mediated CRC development. I discovered that the existing FimH-inhibitor Sibofimloc (Enterome), which is currently in clinical trial for IBD, effectively prevents epithelial binding and CRC progression. However, continuous Sibofimloc treatment is necessary to offer sustainable protection (Jans & Kolata et al., Nature, in press).

 

My proof-of-concept findings indicate that anti-adhesive therapies are essential to prevent E. coli driven CRC development. In this this translational research project application, I will validate novel innovative pharmacological strategies to target pks+ E. coli during CRC development.  Such therapies hold the potential to enhance the treatment and prevention of colorectal cancer, ultimately offering new hope and improved outcomes for patients.