Drug that targets an inflammatory enzyme could help prevent lung cancer

Every year, lung cancer kills more than 100,000 people in the United States. Smoking is the leading risk factor for lung cancer, but other environmental exposures can also contribute to the disease.

In an advance that could help prevent some of those lung cancer deaths, MIT researchers have shown that blocking an enzyme involved in lung inflammation appears to reduce the risk of developing tumors.

The researchers found that this enzyme, caspase-1, is active in developing tumors in mice. When they treated the mice with a small-molecule drug that inhibits caspase-1, the mice were much less likely to develop lung tumors.

That drug has already entered clinical trials for other diseases, and the researchers now hope to test it as a preventive drug in people at elevated risk for lung cancer.

“If you look at global cancer deaths, lung cancer causes most of them, and most of that is driven by tobacco smoking,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science (IMES).

“Additionally, people who are ‘never smokers’ are showing up with lung cancer. You can imagine a future where you get a test and if you’re deemed high-risk, you go on a preventive medicine. This concept is called cancer interception, and it could help millions of people.”

Bhatia is the senior author of the new study, which appears in Science Advances. Cathy Wang, Ph.D., is the lead author of the paper.

Blocking inflammation

Preventing lung cancer in patients who are at high risk could significantly reduce the disease’s death toll. In 2017, a clinical trial conducted by Novartis yielded a tantalizing hint that targeting lung inflammation could prevent some lung cancer cases.

That trial, known as CANTOS, was designed to examine whether an anti-inflammatory drug—an antibody that blocks the cytokine IL-1 beta—could reduce the risk of strokes and heart attacks. Unexpectedly, the researchers found that this treatment led to lower rates of lung cancer in a subset of people.

Later trials showed that the antibody had little effect in patients who had established lung cancer, but researchers are still exploring the possibility of using it to prevent lung cancer progression in high-risk patients.

A recent study by the Swanton lab at the Francis Crick Institute identified a set of proteins, across several biological pathways and cell types, that could be used to predict which patients would respond to treatment with an IL-1 beta antibody.

IL-1 beta requires protease cleavage to be converted to its mature, active form. Thus, Bhatia and her team wondered whether enzymes called proteases, which cleave other proteins, might be involved in driving the inflammatory pathway that includes IL-1 beta.

For several years, Bhatia’s lab has been developing tools to track and visualize proteases, since the activity of these enzymes can contribute to cancer development. Proteases can help tumor cells escape their original locations by cutting through proteins of the extracellular matrix, and they also play essential roles in guiding inflammatory cell migration, which can influence tumor growth and immune system targeting.

By developing ways to detect these enzymes, Bhatia’s lab has created diagnostic nanosensors for cancer and other diseases. The sensors consist of nanoparticles decorated with peptides that can be cleaved by certain proteases, revealing when proteases are active in a particular tissue or disease state.

In addition to their role in cancer, proteases are known to be involved in the regulation of inflammation. In their new study, Bhatia and her colleagues adapted their nanosensors to identify proteases that may participate in IL-1 beta-mediated inflammatory pathways.

“We know that proteases are very important in inflammation, and we wanted to pinpoint which ones might be the most active during early lung cancer development,” Wang says.

For this study, the researchers used a mouse model developed by Tyler Jacks, the David H. Koch Professor of Biology at MIT and a member of the Koch Institute. This model, known as KPS, is engineered to turn on cancer-causing mutations in the p53 and Kras genes. The mice also express a peptide called SIINFEKL, which helps activate T cells and stimulate inflammation in the lung.

The researchers designed their experiments to allow them to model increased cancer risk, beginning before tumor formation was detectable. Five weeks after they induced the cancer-causing mutations, the researchers injected some of the mice with an antibody that blocks IL-1 beta, while others were untreated. Three weeks later, the researchers used their nanosensors to detect proteases that were active in the lungs.

Those experiments showed that in untreated mice, which all developed lung tumors, caspase-1 was very active. However, in the treated mice, which had fewer tumors, caspase-1 activity was significantly reduced. The researchers also found that in untreated mice, active caspase-1 was found primarily in lung tumors, not in nearby healthy tissue.

Working with Lecia Sequist, a professor of medicine at Harvard Medical School and physician at Mass General Brigham, the researchers also analyzed a small number of human lung fluid samples. In these samples, they found higher levels of caspase-1 activity in samples from patients with lung cancer than in samples from healthy donors, despite a common smoking history.

A repurposed drug

The observation that caspase-1 activity is linked to the IL-1 beta inflammation pathway was not completely surprising, given that IL-1 beta itself requires protease cleavage to be converted to its mature, active form. The MIT team then investigated whether inhibitors of caspase-1 might also provide the same protective effects as inhibitors of IL-1 beta, or even improve them.

Before tumors developed, the researchers began treating the at-risk KPS mice with either a caspase-1 inhibitor, an IL-1 beta antibody or both. In mice that received both drugs, nearly 20% never developed tumors at all. In the mice that received either the caspase-1 inhibitor or the IL-1 beta antibody alone, tumors were much smaller and less numerous than in untreated mice.

Unlike antibodies, which need to be given intravenously, caspase-1 inhibitors can be taken orally, which could make them more appealing as a preventive treatment. Another opportunity provided by these drugs is that they have previously been tested in clinical trials for the treatment of rheumatoid arthritis and other diseases.

“What’s so attractive about using this caspase-1 inhibitor is that it has actually been tested in humans. It’s already been through safety studies, and we think it could potentially be repurposed for cancer prevention,” Bhatia says.

The researchers hope to test the drug in a clinical trial, potentially using the biomarkers identified by the Swanton team to identify participants likely to respond to IL-1 beta antibody treatment.

The authors of the study also include MIT researchers Qian Zhong, Shih-Ting Wang, Carmen Martin-Alonso, Sofia Neaher, Sahil Patel, Tiziana Parisi, Jesse Kirkpatrick and Jacks.

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

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