Research raises hope for colon cancer prevention drug

Most experts say colon cancer is a multistage disease driven by the accumulation of genetic mutations.

Not Scott A. Waldman. The Thomas Jefferson University researcher has spent decades bolstering the iconoclastic idea that colon cancer is basically a hormone-deficiency disease - one that can be reversed or even prevented by restoring the hormone.

Now, Waldman's team has also linked that hormone, called guanylin, to obesity, offering a clue to why obese people are at increased risk of colon cancer.

The latest study, like some previous ones, was conducted in mice, so the results have to be interpreted cautiously.

Still, the implications are so promising the National Cancer Institute is funding human testing of Linzess, a novel constipation therapy that is structurally similar to guanylin, in hopes that the drug can help prevent colon cancer. Researchers from the Mayo Clinic and Fox Chase Cancer Center are collaborating.

"We know mice are not perfect models of men," said Waldman, a molecular pharmacologist. "But we have measured the [guanylin] hormone production in skinny and obese people, and obese people mimic the hormone loss in fat mice."

Cancer of the colon, or large intestine, is the third most commonly diagnosed malignancy worldwide, and the fourth most deadly, with 2.2 million new cases projected by 2030, according to a new analysis in the journal Gut.

Guanylin is part of a gene-signaling pathway that normally suppresses intestinal tumor development. After guanylin is produced in cells lining the intestines, it binds to and activates an intestinal cell receptor called GCC that helps regulate cell growth.

Over many years, Waldman and colleagues have used cell cultures and animal models to decipher guanylin's action. A shortage of the hormone turned off the GCC receptor, triggering uncontrolled intestinal cell growth. In mice that developed cancer, guanylin production was always lost. (In 2014, the researchers also showed the hormone was missing in tumors from 54 colon cancer patients, but present in 30 normal colon specimens.)

Conversely, restoring production of guanylin in mice reversed the abnormal cell growth and warded off cancer.

The latest experiments aimed to explore why obese people are about 50 percent more likely to develop colon cancer than lean people. Conventional thinking is that fat tissue disrupts metabolic processes, triggering inflammation and other damaging responses.

The study - done with scientists from Harvard and Duke Universities and published last month in the journal Cancer Research - fed varying diets to genetically altered mice. As theorized, diet-induced obesity often caused a loss of guanylin, leading to tumor development. This damage was reversible by restoring guanylin through calorie restriction. Excess calories, the researchers discovered, turned off guanylin by stressing a specialized subunit of intestinal cells that helps synthesize proteins and fats.

To verify that hormone deficiency rather than obesity was the culprit, the researchers engineered mice to carry a gene that prevented the guanylin gene from being shut off. That meant guanylin production couldn't be suppressed, no matter how fat the rodents grew. Sure enough, the hormone protected the overfed mice.

"The mice could eat all they wanted but not get colon cancer," Waldman said.

Waldman also believes that a guanylin misfire is to blame when a slim person develops colon cancer, but that obesity makes the problem more likely.

He speculates that obese humans might be able to restore guanylin activity through calorie restriction - "the challenges of lifestyle modification notwithstanding."

The National Cancer Institute-funded research aims to test an alternative prevention approach: artificially restoring guanylin using Ironwood Pharmaceutical's Linzess (linaclotide), which treats chronic constipation and irritable bowel syndrome by stimulating GCC.

One potential obstacle is that guanylin acts on the whole intestine and rectum, but Linzess acts mostly at the top of the intestine. A pilot trial of 18 healthy volunteers is underway to measure how much of the drug is active in the rectum. If necessary, Waldman said, Ironwood would consider reformulating it.

Although obesity research is full of false leads, he is optimistic this one will pan out.

"The beauty of our findings is that, while we know the hormone is lost in obese mice, its receptors are just sitting there, waiting to be switched on," he said. "These findings suggest that a drug like linaclotide can activate tumor-suppressing receptors to prevent cancer in obese patients."

mmccullough@phillynews.com

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