Colorectal Cancer & Colon Adenomas
Recent findings reveal that the development, growth, and spread of colorectal cancer tumors are influenced by specific bacteria in the large bowel. Among these bacteria are toxin-producing fusobacteria that form biofilms and penetrate the bowel’s surface mucous layer. Some of these bacteria even infect bowel cancers, promoting tumor growth and rendering them more resistant to radiotherapy and chemotherapy.
Reponex is actively working on an innovative drug formulation to combat these cancer-promoting bacteria within the bowel. A preliminary clinical study of RNX-051, conducted at Zealand University Hospital, has successfully enrolled participants, and we anticipate receiving results by the end of 2023. The study has both been performed on cancer tumors and colon adenomas.
Colon adenomas are growths or polyps that develop on the inner lining of the colon (large intestine) and are considered precancerous. These growths are typically benign, meaning they are not cancerous initially, but they have the potential to develop into colorectal cancer over time. Adenomas are considered precancerous because they share some of the genetic and cellular characteristics with colorectal cancer. While most adenomas never progress to cancer, some may undergo changes that lead to malignancy. Therefore, regular colorectal screenings, especially for individuals with risk factors, are crucial for early detection and prevention, as detecting and removing colon adenomas at an early stage can significantly reduce the risk of developing colorectal cancer.
Rationale for developing RNX-051 for colorectal cancer
Fusobacterium is a genus of Gram-negative anaerobic bacteria, species of which, including F. nucleatum, are found in the oral cavity, where they play a role in periodontal disease.
Genomic sequences of fusobacteria have been found to be enriched in colorectal cancer tumors and colon adenomas, with a prominence of DNA sequences related to F. nucleatum. An overabundance of F. nucleatum RNA was also detected in such tumors. Fusobacteria target colorectal adenocarcinoma cells by means of their Fap2 lectin, which specifically binds to the D-galactose-β(1-3)-N-acetyl-D-galactosamine (Gal-GalNAc) residues of the surface carbohydrates of colorectal and certain other adenocarcinomas.
Once in the tumor, the fusobacteria invade the cells and can enhance cellular proliferation, create a tumor-favourable inflammatory environment and protect the cancer cells against killing by natural killer cells and tumor-infiltrating T cells. F. nucleatum also promotes the resistance of colorectal cancers to chemotherapy, and because similar cellular mechanisms are involved, to radiotherapy.
High fusobacterial abundance in colorectal cancer correlates with poor disease outcome. At the same time, there has been a call for antibacterial agents targeted specifically to fusobacteria to avoid the adverse effects of systemically administered broad-spectrum antibiotics.
Fusobacteria are highly sensitive to Reponex preffered antibiotic, which in turn is efficiently transported into intestinal mucosa cells to achieve bactericidal intracellular concentrations within a few minutes of being exposed to high extracellular concentrations. Local administration of the antibiotic via the bowel lumen, will result in a very high antibiotic concentration at the luminal surface of the tumor. The antibiotic penetrates into the tumor cells where the fusobacteria are located to achieve bactericidal concentrations very rapidly, while at the same time being less adequately absorbed into the blood than when given orally or systemically, so that any systemic adverse effects are reduced.
Quantitative polymerase chain reaction analysis of F. nucleatum DNA in the tumors demonstrates that the bacteria are concentrated in the superficial, luminal portion of the tumors. Therefore, antibacterial treatment by applying a high concentration of the antibiotic from the luminal side should be particularly effective in eliminating the bulk of the bacterial load.