Harvard-led study IDs statin that may block pathway to some cancers

Statins, commonly used cholesterol-lowering drugs, may block a pathway that leads to the development of cancer from chronic inflammation, according to a new study led by investigators from Harvard-affiliated Mass General Cancer Center.

The team’s experiments showed that environmental toxins, such as those caused by exposure to allergens and chemical irritants, create a cascade effect that stimulates inflammation in the skin and pancreas that, when chronic, can result in cancer. Their findings suggest that using statins to suppress this pathway may have a protective effect.

The findings are published in Nature Communications.

In mice, pitavastatin suppressed environmentally induced inflammation in the skin and the pancreas and prevented the development of inflammation-related pancreatic cancers. 

“Chronic inflammation is a major cause of cancer worldwide,” said senior author Shawn Demehri, a principal investigator at the Center for Cancer Immunology and Cutaneous Biology Research Center of Massachusetts General Hospital and an associate professor of dermatology at Harvard Medical School and theBob and Rita Davis Family MGH Research Scholar 2023-2028.

“We investigated the mechanism by which environmental toxins drive the initiation of cancer-prone chronic inflammation in the skin and pancreas. Furthermore, we examined safe and effective therapies to block this pathway in order to suppress chronic inflammation and its cancer aftermath,” Demehri said.

The study relied on cell lines, animal models, human tissue samples, and epidemiological data. The group’s cell-based experiments demonstrated that environmental toxins (such as exposure to allergens and chemical irritants) activate two connected signaling pathways called the TLR3/4 and TBK1-IRF3 pathways. This activation leads to the production of the interleukin-33 (IL-33) protein, which stimulates inflammation in the skin and pancreas that can contribute to the development of cancer.

When they screened a library of U.S. Food and Drug Administration-approved drugs, the researchers found that the statin pitavastatin effectively suppresses IL-33 expression by blocking the activation of the TBK1-IRF3 signaling pathway. In mice, pitavastatin suppressed environmentally induced inflammation in the skin and pancreas and prevented development of inflammation-related pancreatic cancers. 

In human pancreas tissue samples, IL-33 was overexpressed in samples from patients with chronic pancreatitis (inflammation) and pancreatic cancer compared with normal pancreatic tissue. Also, in analyses of electronic health records data on more than 200 million people across North America and Europe, use of pitavastatin was linked to a significantly reduced risk of chronic pancreatitis and pancreatic cancer.

The findings demonstrate that blocking IL-33 production with pitavastatin may be a safe and effective preventive strategy to suppress chronic inflammation and the subsequent development of certain cancers.

“Next, we aim to further examine the impact of statins in preventing cancer development in chronic inflammation in liver and gastrointestinal tract and to identify other novel, therapeutic approaches to suppress cancer-prone chronic inflammation” said Demehri.

Research support was provided by the Burroughs Wellcome Fund, the LEO Foundation, the Sidney Kimmel Foundation, and the National Institutes of Health.