The drug targeted and destroyed cells that contained mutated MSH2 genes. Inherited mutations in MSH2 prevent mistakes in correct copying of DNA during cell division allowing cancer to develop and grow, particularly inherited colorectal and endometrial cancers.  In addition, MSH2 mutations can occur in some colorectal cancers that are not inherited.

Based on the work done in cancer cells, a Phase II clinical trial has begun recruiting patients with advanced colorectal cancer at the Royal Marsden Cancer Hospital in the United Kingdom.  To be part of the trial, patients need to have changes in MSH2 genes either in their tumor tissue or in their blood.

Scientists in the Institute of Cancer Research in London explored the effect of over 1,110 chemicals, most chemotherapy drugs on the market, on cells that lacked a working MSH2 gene and found that methotrexate destroyed DNA and made it impossible for the cells to divide.  Because the MSH2 gene wasn’t functioning to repair DNA mistakes, methotrexate was particularly effective in the deficient cells.

Their goal was to identify drugs or other compounds that could be moved quickly into clinical trials.  Based on the laboratory work,  Professor David Cunningham and his team at the Royal Marsden are recruiting patients with advanced colorectal cancer and mutated MSH2 for a clinical trial to measure their response to methotrexate.  The trial will also measure the time until cancer progresses, overall survival, quality of life, and methotrexate side effects.

Perhaps 40 percent of Lynch syndrome-related colorectal cancers are caused by inherited mutations in the MSH2 gene.  Other genetic mutations known to be connected to Lynch syndrome are found in the MLH1, MSH6, and PMS2 genes.  Although methotrexate targeted and killed MSH2-deficient cells, it was not similarly effective in cell lines with mutated MLH1.

Because Lynch syndrome tumors are microsatellite instable (MSI), they do not respond well to standard treatments with 5-FU.  Methotrexate could provide an alternative treatment that could reduce recurrences in early stage cancers and extend life for patients with advanced cancer.

Professor Alan Ashworth, who led the study, said,

The MSH2 gene plays a vital role in repairing DNA damage but if it is faulty, mistakes accumulate in cells and increase the risk of cancer developing.

What’s exciting about methotrexate is that it selectively destroys the cells lacking the MSH2 function. This indicates that it may make an excellent treatment for patients with the genetic alteration. With our colleagues at The Royal Marsden Hospital, we have set up clinical trials to test this.

Sarah Martin and the team at the Institute of Cancer Research reporting their study in EMBO Molecular Medicine concluded,

While methotrexate has been used for many years as a cancer therapy, our observations suggest that this drug may have particular utility for the treatment of a subset of patients with tumours characterized by MSH2 mutations.

SOURCE:  Martin et al., EMBO Molecular Medicine, online August 27, 2009.

Clinical Trial:  Methotrexate in Metastatic Colorectal Cancer With MSH2 Deficiency (MESH)