Nobel discoveries on DNA repair now fueling cancer drug research

CHICAGO – Cancer researchers are just beginning to understand the ramifications of the fundamental discoveries behind the 2015 Nobel Prizes in Chemistry, which were awarded on Wednesday to three scientists for explaining how cells repair mistakes in DNA that occur when cells divide.

When deoxyribonucleic acid (DNA) repair mechanisms fail, they predispose people to cancer. That is especially true of individuals with mismatch repair defects, a mechanism discovered by Paul Modrich of Duke University and the Howard Hughes Medical Institute.

Modrich, Tomas Lindahl and Aziz Sancar won the prize for "mechanistic studies of DNA repair." Their work mapped how cells repair DNA to prevent damaging errors from appearing in genetic information.

Subsequent work by Dr. Bert Vogelstein of the Johns Hopkins Kimmel Cancer Center and Richard Kolodner, then at Harvard Medical School and currently at the University of California, San Diego, showed mismatch repair defects are the chief cause of the most common inherited form of colorectal cancer, affecting 15 percent of colon cancer patients.

These defects may now help predict which patients are most likely to benefit from immunotherapies, promising new drugs that enlist the immune system to fight cancers.

A small study published earlier this year in the New England Journal of Medicine showed that 92 percent of patients with advanced colon and rectal cancers who had mismatch repair defects responded to Merck & Co's immunotherapy drug Keytruda. That compared to a response of 16 percent in patients with the same cancers who did not carry the defect.

The findings could also be applicable to patients with other cancers who have the same DNA repair defects, and possibly to those with defects in other DNA repair mechanisms as well, Vogelstein said.

"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.

Vogelstein also said mismatch repair is a marker for response to anti-PD-1 inhibitor drugs such as Keytruda because patients with mismatch repair defects have tumors teeming with mutations - far more than cancer patients with functioning DNA repair genes.

Since the immune system is trained to recognize foreign invaders, Hopkins researchers believe immune-boosting drugs such as Keytruda or Bristol-Myers Squibb's Opdivo, will perform better in mutation-loaded tumors.

So far, the findings, while strong, are preliminary. Vogelstein said if this same strategy extends to other cancer types, "it could provide a very useful therapy for as many as one in 50 patients with cancer worldwide."

Dr. Roger Perlmutter, president of Merck Research Laboratories, said "every company that's interested in making drugs that enhance the ability of the immune system to recognize cancer is interested" in exploring DNA repair mechanisms.

"In colorectal cancer, it's unambiguous. Administration of Keytruda is much, much more effective in those people who have DNA repair mutations," he said.

The company is conducting a larger clinical trial in hopes getting FDA approval for the drug in colorectal cancers. Keytruda is already approved in melanoma, and in some forms of advanced lung cancer.

Other drugs targeting DNA repair defects include AstraZeneca���s Lynparza, a so-called PARP inhibitor approved for women with advanced ovarian cancer associated with defective BRCA genes. The drug kills cancer cells by exploiting defects in a tumor DNA repair pathway.

In a blog post earlier this year, Dr. Francis Collins, director of the National Institutes of Health, noted that most of the original work on DNA repair mechanisms was done in bacteria, "with no expectation of medical relevance."

Vogelstein said the latest findings in cancer immunotherapies are "a beautiful demonstration of how basic science can have practical value which no one could have seen in the beginning."