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colorectal cancer

A Surprising Match: Cancer Immunotherapy and Mismatch Repair

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Anti-PD-1 Immunotherapy

How Anti-PD-1 Immunotherapy Works. Before immunotherapy (top), the tumor cell’s PD-1 ligand, or PD-L1, molecule (red) binds to a type of white blood cell called a T-cell in a way that enables the tumor cell to evade destruction by the immune system. During immunotherapy (bottom), an anti-PD-1 inhibitor drug (bright green) blocks PD-L1 binding, enabling the T cell to target the tumor cell for destruction.
Credit: NIH

Mismatch repair genes have long been a source of fascination to basic biologists. Normally, these genes serve to fix the small glitches that occur when DNA is copied as cells divide. Most of the original work was done in bacteria, with no expectation of medical relevance. But, as often happens, basic science studies can provide a profoundly important foundation for advances in human health. The relevance of mismatch repair to cancer was dramatically revealed in 1993, when teams led by Bert Vogelstein of Johns Hopkins University School of Medicine, Baltimore, and Richard Kolodner, then of Harvard Medical School, Boston, discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer [1, 2].

That discovery has led to the ability to identify individuals who have inherited misspellings in these mismatch repair genes and are at high risk for colorectal cancer, providing an opportunity to personalize screening by starting colonoscopy at a very early age and, thereby, saving many lives. But now a new consequence of this work has appeared. Vogelstein and his colleagues report that mismatch repair research may help fight cancer in a way that few would have foreseen two decades ago: predicting which cancer patients are most likely to respond to a new class of immunotherapy drugs, called anti-programmed death 1 (PD-1) inhibitors.


Precision Medicine: Who Benefits from Aspirin to Prevent Colorectal Cancer?

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Aspirin and DNA StethoscopeIn recent years, scientific evidence has begun to accumulate that indicates taking aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) on a daily basis may lower the risk of developing colorectal cancer. Now, a new study provides more precise information on who might benefit from this particular prevention strategy, as well as who might not.

Published in the journal JAMA, the latest work shows that, for the majority of people studied, regular use of aspirin or NSAIDs was associated with about a one-third lower risk of developing colorectal cancer. But the international research team, partly funded by NIH, also found that not all regular users of aspirin/NSAIDs reaped such benefits—about 9 percent experienced no reduction in colorectal cancer risk and 4 percent actually appeared to have an increased risk [1]. Was this just coincidence, or might there be a biological explanation?


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