Earlier this year, Dr. Francis Collins, Director of the National Institutes of Health noted in his blog post, “DNA repair mechanisms have been extensively studied on bacteria over the past decades, with no expectation of medical relevance.”
However, the 2015 Novel discovery on DNA repair mechanism has shown to be “a beautiful demonstration of how basic science can have practical value which no one could have seen in the beginning”, says Dr. Bert Vogelstein from Johns Hopkins Cancer Center. This discovery has shown the capability to identify patients who can be greatly benefited by immune-boosting drugs and is foreseen to fuel the cancer immunotherapy drug discovery in future.
In early October, Paul Modrich (discovered mismatch repair), Thomas Lindahl (discovered base excision repair), and Aziz Sancer (discovered nucleotide excision repair) were awarded the 2015 Nobel Chemistry Award for mapping out how cells repair damaged DNA and safeguard the genetic information at a molecular level. They have demonstrated that the failure of DNA repair mechanism can make people susceptible to cancer, especially for people with mismatch repair defects.
Subsequently, Vogelstein found that mismatch repair defects are the chief cause of the most common inherited form of colorectal cancer, affecting 15% of colon cancer patients. Researchers believe these defects might be further used as markers to identify patients who will be mostly benefitted by cancer immunotherapy, as immunotherapy will work better on those particular tumors swarming with mutations.
Infact, a study published in New England Journal of Medicine demonstrated that 92% colon and rectal cancer patients could respond to an immunotherapy Keytruda when carried mismatch repair defects; while such response dropped to only 16% of the same cancer patients without the defect.
In addition, Vogelstein also suggested that these findings can be potentially applied to other cancers where patients have the same DNA repair defects, or those with defects in other DNA repair systems as well. “Mismatch repair defects are found not only in hereditary colorectal cancers. They are found in about 2 percent of cancer patients overall,” he said in a telephone interview, “it could provide a very useful therapy for as many as one in 50 patients with cancer worldwide.”
Although these results are still preliminary, the data on Keytruda is quite solid in defective DNA repair colorectal cancer patients. On top of that, other drugs that target DNA repair defects such as Lynparza from AstraZeneca has already been proved by FDA to treat ovarian cancer patients with defective BRCA genes.
DNA repair mechanism will be the next research hot spot for immuno cancer drug discovery, “every company that’s interested in making drugs that enhance the ability of the immune system to recognize cancer will be interested in exploring DNA repair mechanisms”, says Dr. Roger Perlmutter, President of Merck Research & Laboratories.