Treating Colon Cancer By Activating Damaged Genes

What if doctors could turn cancer cells into healthy cells? It would change everything about how we treat cancer. Researchers may have discovered a way to do that in colorectal cancer.

What if we could turn the clock back on cancer cells and return them to their healthy status?   A new study in animals might have accomplished exactly that.

A research team from the Memorial Sloan Kettering Cancer Center has reactivated a defective gene in mice with colorectal cancer.  This gene, adenomatous polyposis coli, or Apc, is commonly defective in colorectal cancer cells.  Approximately 90 percent of colorectal tumors have a loss-of-function mutation of this gene.

At the onset of this research project, The Sloan Kettering group suppressed the expression of the Apc gene in mice.  The Apc gene encodes a protein that regulates an important cell signaling pathway known as the Wnt signal pathway.  Suppression of Apc activates the Wnt signaling pathway, which helps cancer cells grow and survive.

Afterwards, they reactivated the Apc gene, which returned Wnt signaling to its normal levels and the cancerous tumors stopped growing, and normal intestinal function was restored in four days. By two weeks after Apc was reactivated, the tumors were gone and there were no lingering signs of no signs of cancer relapse during the six-month follow-up.

The same approach turned out to be effective in mice with colorectal cancer tumors that result from activating mutations in the Kras gene and loss-of-function mutations in the p53 gene.  In humans, about half of colorectal tumors have these mutations

This study was published in the prestigious international journal, Cell, by Scott Lowe and his colleagues.  “Treatment regimens for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective, yet have remained the backbone of therapy over the last decade,” said Lowe.

Apc reactivation might very well be the way to improved treatment for colorectal cancer.  It is doubtful it will be helpful in other types of cancer, but in the future, it might become so.  “The concept of identifying tumor-specific driving mutations is a major focus of many laboratories around the world,” said Lukas Dow, Ph.D., of Weill Cornell Medical College, who is the first author of this study.

“If we can define which types of mutations and changes are the critical events driving tumor growth, we will be better equipped to identify the most appropriate treatments for individual cancers,” said Dow.

Colorectal cancer begins in the colon or rectum, and it remains the second-most prevalent cause of cancer death in developed countries.

According to the Surveillance, Epidemiology, and End Results Program, in 2012, there were 1,168,929 people living with colon and rectal cancer in the United States.

Estimates postulate that there will be 132,700 new cases of colorectal cancer in the United States in 2015, and about 49,700 people will lose their lives to this disease. Worldwide, colorectal cancer is the cause of approximately 700,000 deaths each year.

Internist and gastroenterologist Dr. Frank Malkin expressed optimism regarding genetic research into colorectal cancer.  He said in an interview with the medical news service, Healthline: “They’ve identified a suppressor gene that can turn a tumor on and off. It can suppress the cancer and destroy it rapidly. That’s very promising.”

Cancers are normally treated with a combination of surgery, chemotherapy, and radiation.  These rather harsh treatments can take a lasting toll.  Easier and more effective treatments could change the lives of cancer patients.

Michelle Gordon, D.O., FACOS, FACS, finds it encouraging. “If this treatment is to be believed, all current modalities will be obsolete.”

However, Malkin and Gordon both cautioned that it is simply too early to bring this strategy to the clinic to treat human patients.

“There are so many unknowns when taking a mouse model to humans,” Gordon told Healthline. “This may be the foundational step that will lead to curing most colorectal cancers. This study can provide hope to future generations of colorectal cancer [patients], but I believe a cure is decades away.”

Researchers know Apc mutations initiate colorectal cancer, but they are unsure if Apc mutations are involved in promoting tumor growth after the cancer has developed.

The next step in this work will examine the ability of Apc reactivation to affect tumors that have spread or metastasized to distant locations in the body.  Lowe and his colleagues are also hard at work to determine precisely how Apc works.  That will help scientists develop safe treatments that change cancer cells into normal cells. Such a drug could make colorectal cancer treatment easier, faster, and safer.

How this research will impact other types of cancer remains unclear.  “Cure rates for colorectal cancers are better than they used to be, especially when treated in the early stages,” said Malkin.  Nevertheless, it is still far better to stop tumors before they start.

According to Malkin, the number of colon cancer cases has dropped dramatically since routine colonoscopy screening began. A colonoscopy allows doctors to find and remove polyps before they turn cancerous.  Malkin also looks forward to genetic research that will identify those at greater risk for colorectal cancers.

“Right now, we’re using colonoscopy to screen people over 50, most who don’t have the genetic predisposition and will never get colorectal cancer,” he said. “We don’t yet have the genetic studies that would help us identify high-risk patients so we don’t have to screen everyone.”

I must admit that I remain skeptical as to whether or not this will work.  The reasons for my skepticism lie in the fact that tumor cells in the colon are the result of a series of mutations in cells that cause the cells to overgrow and eventually become invasive.  Colorectal carcinoma cells have mutations in several genes and not just Apc.  Apc reactivation worked in these mice because this was the only gene affected in these animals.  In a cancerous human colon, the cancer cells have a variety of mutations.  Kurt Vogelstein’s work at Johns Hopkins has shown this in great detail.  If Lowe could demonstrate the efficacy of his treatment in mice with humanized immune systems that have been infected with human colorectal carcinoma cells, then I will believe that this technique could work in human patients.  For now, I remain skeptical.