Mesalamine for Colorectal Cancer Prevention Program in Lynch syndrome
Patients with Lynch syndrome (LS), defined by having a hereditary mutation in at least one mismatch repair (MMR) gene, have a 50% lifetime risk for the development of colorectal cancer. The incidence of LS in Europe is estimated between 1 in 2000 to 1 in 370 individuals, a population of at least 250.000. Chemoprevention is a big hope for LS family members. Cancer development in LS occurs through a mutational mechanism called microsatellite instability (MSI). The genetic loss of MMR activity induces a mutator phenotype in which genetic deletions occur frequently in repetitive DNA sequences. In vitro, mesalamine (5-ASA), a well-tolerated drug that had been used for over 30 years in ulcerative colitis, reduces MSI via improvement of replication fidelity. In ulcerative colitis it seems to reduce the risk of colorectal cancer. In a genetic mouse model of LS 5-ASA reduced the tumor incidence, tumor multiplicity, and MSI. Here, we propose a multicenter, multinational, randomized, 3-arm, double blind, phase 2, clinical trial with 2400mg 5-ASA, 1200mg 5-ASA or placebo in LS patients for 2 years. Second, we intent to test for synergistic effects of 5-ASA and selected natural compounds (which also reduce MSI in vitro) in a mouse model of LS. Last, we intend to study the molecular effects of 5-ASA on activation of Nrf2, a protein that is involved in cellular stress response and that is activated by 18 out of 20 compounds, which all reduce MSI.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.