Researchers target gene controlling colon cancer stem cells

Researchers target gene controlling colon cancer stem cells
Tue Dec 3, 2013 11:31:02

Canadian scientists believe they have found the "Achilles heel" of colon cancer stem cells, which appear to be responsible for the recurrence of the disease in many patients who have gone into remission after treatment.

Researchers at Toronto's University Health Network have used an experimental drug to disable a gene that regulates these stem cells, which are thought to initiate the development of colon cancer, one of the top-three cancer killers of Canadians.

That gene — known as BMI-1 — has been implicated in maintaining stem cells in other cancers, and is the key regulator of colon cancer stem cells that propels their self-renewal and proliferation.

Stem cells are the blueprints of the body, which give rise to different types of cells that make up tissues, from red and while blood cells to neurons in the brain and insulin-producing cells in the pancreas.

Cancer stem cells, including those identified in the brain, breast and colon, give rise to tissue-specific cancer cells that grow out of control and form tumors.

In Sunday's issue of Nature Medicine, the Toronto researchers describe experiments in which they disarmed the BMI-1 gene, thereby stopping colon cancer stem cells from generating malignant cells.

The team first used a variety of genetic methods to silence the gene in colon cancer cells taken from patients, which were then transplanted into laboratory mice specially bred not to reject human tissue.

"And it just wiped out the ability of these cells to make new tumors," said principal researcher John Dick, a senior scientist at Princess Margaret Cancer Centre and director of the cancer stem cell program at the Ontario Institute for Cancer Research.

"We showed that if you turn this thing down, the colon cancer stem cells, they're not stem cells anymore. They lose their function."

The team then took human colon cancer cells — which would have included cancer stem cells in the mix — and exposed them to a drug being developed by a small pharmaceutical company as an inhibitor of the BMI-1 gene and the protein it expresses.

These treated cells were then transplanted into mice with the goal of seeing whether the drug would disable cancer stem cells and stop them from spurring the growth of new tumors.

"And it did," said Dick. "It worked remarkably well."

The team then decided to test the drug by administering it to mice, using the animals as stand-ins for humans. "It's like doing a clinical trial on a human cancer without the human attached," he said.

After transplanting human colon cancer cells into mice, they waited for tumors to develop and then began injecting the rodents with the drug, at first for a couple of days and then over a couple of weeks.

"We showed there was a massive reduction in tumor growth when we treated the mice with the drug," said Dick.

Remnants of tumor left in those mice were then transplanted into a second set of mice, and "low and behold, the cancer stem cells were markedly reduced by exposing them to the drug," he said.

"So that, in essence, is the paper. It's essentially saying we found the Achilles heel for a colon cancer stem cell. We've shown in a therapeutically relevant way that we can target cancer stem cells."

For decades, traditional cancer treatment has been based on therapies aimed at killing the fast-dividing cells that form tumors. But those therapies do not always result in permanent eradication of the malignancy.

In the case of colon cancer, for instance, about half of people get a recurrence of the disease, and many scientists believe that's because previously quiescent cancer stem cells are reactivated and "self-renew" to give rise to new cancer cells that once again proliferate into tumors.

"What we're saying is self-renewal is now a target," Dick said.

Dr. Catherine O'Brien, a surgeon-scientist and senior co-author of the study, said the research potential "maps a viable way to develop targeted treatment for colon cancer patients."

"It is already known that about 65 per cent have the BMI-1 biomarker. With the target identified, and a proven way to tackle it, this knowledge could readily translate into first-in-human trials to provide more personalized cancer medicine," she said.

Neurosurgeon Dr. Sheila Singh, a principal investigator in the Stem Cell and Cancer Research Institute at McMaster University, said the earlier discovery by Dick's lab of a leukemia stem cell has inspired solid tumor researchers — in her case, brain tumors — to investigate stem cells as a potential treatment target.

"The nice thing is that with this approach, applying stem cell biology to cancer biology, what you're looking at are genes that regulate normal self-renewal, like BMI-1," Singh, who was not involved in the study, said from Hamilton. "Now (they are) finding it is also a valid target for colon cancer."

"I think it's quite a breakthrough that they've been able to apply that same concept of therapeutic targeting to a solid cancer."

"This is essentially a landmark paper," concluded Nicole Beauchemin, a cancer biologist at McGill, who also was not involved in the research.

"What they have done that is novel is to be able to show what the role of this (BMI-1) protein is in the stem cells," Beauchemin, who studies colon cancer, said from Montreal.

"So it's validating the cancer stem cell hypothesis, at least in colon cancer, as a source of a very significant problem relevant to the development of the tumor, but also to the recurrence of the tumor and the possible resistance of the tumor to (traditional chemotherapy) drugs."

By inhibiting BMI-1, she said the researchers have demonstrated that a drug might be refined for patients that could stop colon cancer stem cells in their tracks.

The next step is for pharmaceutical companies to come up with BMI-1 inhibiting drugs that could be tested for safety and effectiveness in people.

"The step into the first clinical trials will be sooner than later," said Dick, a basic scientist who tests drugs but is not involved in their development.

As to when a drug might be on the market, he said he can't predict that for certain. "Not this year, but likely within 10."