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 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.
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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."
(Reporting by Julie Steenhuysen, editing by G Crosse)
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