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Surprise discovery suggests new stomach cancer option

Researchers studying lupus discovered that treatments similar to those already in use to treat melanoma and lung cancer, including immunotherapy, show promise for stomach cancer and may even lead to preventative treatments.

Usually the symptoms of stomach—or gastric—cancer are hard to pick up until it’s too late, making what is a relatively common cancer an often fatal one.

Survival rates are low, and the main treatments are drastic—surgery to remove all or part of the stomach, usually followed by chemotherapy and radiotherapy.

Spontaneous and invasive

Lorraine O’Reilly, a researcher at the University of Melbourne, was working on the autoimmune disease lupus when she noticed some mice started to develop stomach tumors at around 12 to 18 months of age.

“When I consulted our pathologist, professor Paul Waring from the University of Melbourne, he didn’t believe me at first,” O’Reilly says. “However, after reviewing the slides he sent me an enthusiastic email that afternoon asking to be involved in the project.”

These weren’t normal mice—they had been purposely bred without the gene NF-KB1. When the molecular immunologist and her colleague Tracy Putoczki investigated further, they discovered that removing this gene actually caused spontaneous development of malignant stomach cancer, driven by chronic inflammation.

“This was the first time we’ve seen spontaneous invasive stomach cancer in mouse models, but the amazing thing was that NF-KB1 gene knock-out models have been around for 20 years without anyone realizing this,” O’Reilly says.

“Interestingly, we saw the cancer develop in an equivalent time frame to what you would see in humans, that is between 50 and 70 years. “Of course, after this initial discovery, we tweaked the model to improve its use as a preclinical model for testing therapies, making it truly unique.”

The finding was particularly surprising because NF-KB1 belongs to a family of proteins otherwise known to drive cancer development, not prevent it, making NF-KB1 the “odd one out,” O’Reilly adds.

Inflammatory cells

It is well established that although stomach cancer in humans can take decades to present, the inflammation—or gastritis—that causes it appears much earlier. The inflammation can begin in various ways, including infection with the bacteria H.pylori or Epstein-Barr Virus, or even a high salt diet. More recently a genetic link to abnormalities in the NF-KB1 gene have been documented in some gastric cancer patients.

“Inflammatory cells produce proteins called cytokines, which will cause cells to grow and divide more rapidly. Over a long period of time, this often leads to DNA damage and mutations, which is how most inflammation-induced cancers, like colon cancer and stomach cancer, develop,” O’Reilly says.

It took six years from their initial discovery for O’Reilly and colleague Tracy Putoczki to work out exactly how loss of NF-KB1 caused cancer development.

“Because the sequence of events leading from chronic inflammation to gastric cancer in our models is so similar to how it develops in humans, we have been able to get a better understanding of how the disease develops and new insights into potential treatments,” O’Reilly says.

The researchers found signs of inflammation at the molecular level long before the tumors emerged in the “NF-KB1 knockout” mice. These signs included high levels of proteins like cytokines and so-called STATS (Signal Transducer and Activators of Transcription), in particular STAT1.

They are now investigating inhibiting different STATS as a way to dampen down the early inflammation to prevent tumors forming in the first place.

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“We have now shown that loss of STAT1 is a very promising in preventing inflammation associated with gastric cancer development. Currently there are no really good STAT1 inhibitors for human therapy but if this works out it might be an impetus for drug developers,” she says.

They also discovered that a protein called PD-L1 is expressed or activated in certain immune cells long before the cancer appears. PD-L1 sends a signal that prevents infection fighting T-cells from responding to a tumor. Existing immunotherapies used for lung and skin cancers block these signals to allow the T cells to kill the tumor.

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“Finding increased levels of PD-L1 makes stomach cancer a classic target for existing immunotherapies. But because we have been able to understand more about the genetics of this disease, we have identified a range of other potentially good candidates for new therapies that could expedite clinical trials of treatments for gastric cancer patients.”

The findings appear in Immunity. The researchers are now looking into exactly which combinations of drugs will offer effective treatments for stomach cancer.

Source: University of Melbourne

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