The Story of APC
A rare genetic mutation provides insight into treating colon and other cancers.
Painkillers such as aspirin and the much lesser-known sulindac were initially created to treat patients with arthritis. But in the 1980s, William Wadell, a doctor in Denver, Colorado, made a startling discovery. He had been treating a patient for a genetic condition linked to the development of colon cancer. That patient had already undergone a colectomy, or removal of the colon, to thwart the cancer, but then developed rectal polyps. By chance, the patient was also prescribed sulindac to treat a tumor. After six months, Wadell noticed that the patient’s rectal polyps had begun to shrink. Could, he wondered, patients predisposed to colon cancer ward off the disease by taking a regular dose of painkillers?
Many cancers, including those of the colon, arise from mutations in the APC gene. This is not surprising as APC is like a housekeeper, organizing, tidying, discarding -it helps regulate how cells grow, mature, and destruct. As a result, mutations in the APC gene are found in many cancerous cells, such as those lining the colon, blood stream, or breasts.
Typically, adults acquire an APC mutation as they age and are exposed to carcinogens in the environment. Occasionally, though, individuals inherit an APC mutation from a parent in a condition called familial adenomatous polyposis, or FAP – the same condition afflicting Wadell’s patient. FAP appears in anywhere from 1in 7000 to 1 in 22000 adults. For people with this condition, polyps begin to appear on the colon by around age 16 and rapidly increase in number and size. If the colon, or colon and rectum, are not removed in time, colon cancer becomes inevitable.
Other rarer mutations in the APC gene can also be hereditary. Two-thirds of patients with Turcot Syndrome, a condition marked by cancer of the brain and colon, have a mutation. Similarly, about 6 percent of people with Ashkenazi Jewish heritage carry a mutation in the APC gene that increases their risk of developing colon cancer by about 10 to 20 percent.
Even though inherited APC mutations are rare, researchers hope that by studying such conditions, particularly FAP, they will learn how to monitor and treat people with APC mutations in the larger population. If a treatment “works in FAP, then it would make sense to do a similar study in people who develop garden variety polyps in garden variety cancer,” says Patrick Lynch, a professor of gastroenterology at The University of Texas MD Anderson Cancer Center in Houston.
Physicians have known about FAP for over a century -before words like cancer and DNA entered the lexicon. Early practitioners could identify the disorder’s symptoms, such as bloody stool, diarrhea, abdominal pain, and weight loss (such symptoms appear during the disease’s later stages), but didn’t know the source of the problem.
Then in 1991, researchers from two labs independently cloned and described the APC gene. Mutations to the APC gene were subsequently linked to patients with FAP. Further research has shown that the location of the mutation on the DNA strand determines when a person with FAP will begin developing polyps. Such genetic markers may influence how the disease is managed one day.
Researchers also began looking into the proteins under the APC gene’s control. They realized that the APC protein acts as a tumor suppressor by preventing cells from growing and dividing without control. Like the master switch in a house, the APC protein regulates how often a cell divides, how it attaches to other cells within a tissue, and whether or not a cell enters a tissue.
Because it can’t accomplish all those tasks alone, the APC protein interacts with several other proteins, most crucially a protein known as beta-catenin. When beta-catenin is done helping cells proliferate and specialize, the APC protein sends out a signal for it to destruct. But in patients with a mutated APC gene, the APC protein is the wrong shape. That means it can’t bind to proteins like beta-catenin. Consequently, the beta-catenin runs amok, resulting in cancer.
For those with a family history of colon cancer, or a parent with FAP, it’s now common to conduct genetic tests on children as young as 8 years old. All that’s required is a simple blood test. That way, if a child doesn’t carry the APC mutation, they won’t have to be subjected to regular monitoring and painful procedures such as colonoscopies. For those that test positive, regular surveillance starting in the early to mid teens becomes crucial.
Meanwhile, researchers continue to look for ways to slow the polyps’ formation and progression to cancer. After observing the effect of the sulindac on one of his patients with FAP, Wadell gave the drug to several of the patient’s family members, a well as a few other FAP patients in his care. Many had already had their colons removed, but had developed subsequent polyps on the rectum. After a year on sulindac, Wadell reported that the majority of the patients’ polyps had disappeared. Those leftover were small and flat.
Wadell’s study, which included just 10 individuals including 7 from the same family, was decidedly small. But it triggered a flurry of research into the potential for drugs known as non-steroidal anti-inflammatory drugs, or NSAIDs, to thwart colon cancer.
While the precise mechanism of how NSAIDs work is not fully understood, it is known that they block the COX-1and COX-2 genes. What’s more, knocking out the COX-2 gene in animal models, such as mice with a mutated APC gene, dramatically reduces their polyp count. That finding prompted researchers to test NSAIDs that selectively targeted the COX-2 gene in patients with FAP. (Sulindac and aspirin are more general and target both COX-1 and COX-2 genes). A study in 2000 showed that when 77 patients with FAP took a COX-2 inhibitor known as celecoxib (marketed as Celebrex) they experienced, on average, a 28 percent reduction in polyp count and a 31 percent reduction in polyp size. That prompted the Food and Drug Administration (FDA) to approve celecoxib and another similar drug rofecoxib (marketed as Vioxx) as a treatment for patients with FAP.
But subsequent studies showed that the two drugs tripled the risk of heart disease in long-term users. Rofecoxib has since been pulled from the market while celecoxib comes with an FDA mandated black-box warning.
Now researchers have been looking to aspirin, which is non-selective and already widely prescribed to people at risk of developing heart disease. Results so far have been promising, although proper dosage has yet to be determined. (The lower the dose, the lower the likelihood of toxicity). Others are looking at combining low -and hopefully safe -doses of an NSAID with other drugs or supplements, such as calcium, to both minimize side effects and increase effectiveness.
The holy grail is to one day find a way to fix the faulty APC protein in people with a mutation in the gene. Using drugs to prevent polyps occurs very late in the game, says Lynch. “You’re locking the barn door after the horse has escaped.”But the creation of such a drug, as well as sorting out how to deliver it into the body, is still a long way off.
Meanwhile, buoyed in part by research into treating patients with FAP, some researchers have been looking to see if supplements like fish oil or regular aspirin use can slow the spread of colon cancer in the general population.