Mouse study suggests new therapeutic strategy to reduce cardiovascular disease in cancer survivors

Mouse study suggests new therapeutic strategy to reduce cardiovascular disease in cancer survivors

Newswise – Researchers at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York have discovered that common cancer treatments such as radiation therapy or anthracyclines cause long-term damage to heart tissue by activating a key inflammatory signaling pathway. The study, published December 19 in the Journal of Experimental Medicine (JEM), suggests that inhibiting this pathway could reduce the chances of cancer survivors developing heart disease later in life.

Many cancers are treated with radiation and/or drugs that kill tumor cells by causing breaks in their DNA. But these treatments also damage the DNA of the patient’s healthy cells. As cancer patient survival rates continue to increase, the long-term consequences of this are of growing concern. For example, radiation therapy or a class of DNA-damaging drugs known as anthracyclines can have delayed, toxic effects on the heart and increase the risk of developing cardiovascular disease, including coronary artery disease or heart failure. One study found that the incidence of cardiovascular disease in long-term Hodgkin lymphoma survivors is five times higher than in the general population.

“The mechanisms by which DNA damage leads to late tissue toxicity years after cancer treatment are poorly understood,” says Adam M. Schmitt, radiation oncologist at MSKCC. “Identifying the pathogenic mechanisms of toxicity and early biomarkers of their activation would provide an opportunity to intervene in treatment to prevent toxicity.”

In their study, Schmitt and colleagues found that a month after mice were exposed to either radiation or anthracyclines, a specific population of heart cells called fibroblasts activated a set of genes that promoted recruitment of various immune cell types associated with pathological inflammation and tissue fibrosis . Within 3-6 months the mice developed signs of cardiac dysfunction and by 12 months many of them had died of heart failure.

The researchers found that this pathological process is driven by an immune signaling pathway called the cGAS-STING pathway. This pathway normally promotes inflammation in response to DNA fragments derived from pathogenic bacteria or viruses, but Schmitt and colleagues argued that it could also be activated by DNA fragments generated in response to radiation or anthracycline treatment.

Mice lacking either the cGAS or STING protein were protected from the toxic side effects of DNA-damaging cancer treatments. They showed no signs of heart inflammation, maintained normal heart function, and lived a year after treatment. A small molecule inhibitor of the STING protein also protected mice from the toxic effects of radiation therapy or anthracyclines.

By studying breast cancer patients treated with anthracyclines, Schmitt and colleagues found evidence that the cGAS-STING signaling pathway may play a similarly important role in human cardiac toxicity. One of the key inflammatory proteins induced by cGAS-STING signaling is CXCL10, and the researchers found that patients who showed the largest increases in CXCL10 levels after treatment with anthracyclines subsequently showed changes in echocardiograms that been associated with cardiac toxicity.

“Taken together, our data show that targeting the cGAS-STING pathway has great potential as a treatment to prevent cardiac complications from DNA-damaging cancer treatments,” says Schmitt. “These data indicate that clinical trials of cGAS-STING inhibitors for the prevention of cardiovascular disease following DNA-damaging cancer therapy are warranted.”

Shamseddine et al. 2022. J. Exp. Med.

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above Journal of Experimental Medicine

Journal of Experimental Medicine (JEM) publishes peer-reviewed research in immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions on research manuscripts are made in collaboration between professional scientific editors and the academic editorial board. founded in 1896, JEM is published by Rockefeller University Press, a division of Rockefeller University in New York. Visit for more information.

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