Pitavastatin Offers Therapeutic Potential in Cancers Arising From Chronic Inflammation

Shadmehr Demehri, MD, PhD

The statin pitavastatin (Livalo) could potentially inhibit the production of IL-33, which often contributes to the development of cancer via chronic inflammation, according to findings published in Nature Communications.

“Fifteen to 20% of cancer deaths worldwide relate to cancers that develop in the context of chronic inflammation; we set out to determine what factor initiates the development of chronic inflammation in various organs,” Shadmehr Demehri, MD, PhD, director of the High Risk Skin Cancer Clinic at Massachusetts General Hospital, as well as an associate professor of dermatology at Harvard Medical School in Boston, Massachusetts, and senior study author, said in a statement to OncLive^®. “Based on our discovery that IL-33 is the driver of cancer-prone chronic inflammation we investigated the cellular mechanism that regulates the expression of this immune factor. Our findings, reported in the current report, reveal this mechanism and demonstrates how [a] statin drug can block this immune factor expression in experimental models and prevent chronic inflammation and cancer in them.”

Findings from preclinical study conducted in cell lines, animal models, and human tissue samples, as well as epidemiological data, indicated that environmental factors activate the TLR3/4 and TBK1-IRF3 signaling pathways, which in turn lead to the production of IL-33. IL-33 has been shown to contribute to inflammation of the skin and pancreas, which can subsequently add to the development of cancer. Investigators subsequently identified pitavastatin as an effective blocker of the TBK1-IRF3 signaling pathway and noted that the statin suppressed skin and pancreatic inflammation caused by environmental factors in mice.

After performing a review of data from over 200 million patients across 92 health care networks in North America and Europe investigators showed that pitavastatin significantly decreased the risk of chronic pancreatitis compared with ezetimibe (Zetia; OR, 0.81; 95% CI, 0.729-0.9; P < .0001). Moreover, patients who received pitavastatin also experienced a significant decrease in their risk of developing pancreatic cancer compared with those who were treated with ezetimibe (OR, 0.835; 95% CI, 0.748-0.932; P = .0013).

“[These findings] are very noteworthy because effective cancer prevention requires novel strategies that are first and foremost safe for use in patients,” Demehri said. “Here, we show how a very safe drug that is used by many patients for long duration to lower their cholesterol, statin, can provide cancer prevention in at-risk patients. In other words. we provide an innovative approach for cancer prevention, which is safe and actionable for use in humans.”

To conduct their study, Demehri and coauthors first subjected wild-type mice to established models of chronic skin and pancreatic inflammation to establish the mechanism of IL-33 induction in chronic inflammation. They then used cell lines to show that TBK1-IRF3 signaling regulated IL-33 expression.

To identify pitavastatin as a potential IL-33 inhibitor, study authors screened 1018 small molecules that had been approved by the FDA and found that the statin suppressed IL-33 expression of Pam212 cells as well as PyMttg breast cancer cell lines, which had high expression of IL-33 at baseline. Investigators compared matched cohorts of patients from the TriNetX Diamond Network to examine the effect of treatment with pitavastatin on chronic pancreatitis and pancreatic cancer incidence.

Expanding on safety considerations for patients, Demehri noted that the statin approach could be an attractive treatment option due the extensive safety data that are available with the agents in cardiovascular disease. Statins represent an attractive candidate for safe cancer prevention and prospective clinical trials are warranted to directly test statin benefit in terms of cancer prevention in populations at a high risk of developing cancer, he added.

“It is critical to examine statin efficacy for cancer prevention in chronic inflammation directly in patients through clinical trials,” Demehri said in conclusion. “We also aim to extend our work to encompass the array of chronic inflammatory diseases that render patients prone to cancer (example: ulcerative colitis and hepatitis) in order to help prevent cancer in all patients affected by chronic inflammation.”

Reference

Park JH, Mortaja M, Son HG, et al. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nat Commun. Published online May 30, 2024. doi:10.1038/s41467-024-48441-8