MesaCapp

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.

Patients with an inheritable form of colon cancer, due to a mutation in a DNA repair gene, have a 50 % change of developing cancer in their lifetime. It is assumed, that 250 000 people in Europe may have this disease, called Lynch syndrome. Prevention of this disease is a big hope for these people. Cancer in these patients occurs due to mistakes in DNA amplification of repetitive DNA sequences, creating mutations. A substance, called mesalamine (5-ASA) reduces these mutations in a cell based system and in a Lynch syndrome mouse model. Within a multinational study we want to investigate 5-ASA for its cancer prevention properties in Lynch syndrome mutation carriers. Also, we want to analyse the preventive effect of 5-ASA and other substances in our cancer mouse model as well as unravel mechanistic effects of 5-ASA at the cellular level.