Rare virus kills cancer cells, Ottawa researchers discover

Cancer cells 'blown away' melanoma, lung, colon, breast and prostate cancers and leukemia

Wednesday 28 June 2000 - Human cancer cells are "completely blown away" by a rare virus that normally causes only minor flu-like infections in people, a team from the University of Ottawa and the Ottawa Regional Cancer Centre has found.

In the laboratory, the virus has destroyed a wide variety of cancer cells, including melanoma, lung, colon, breast and prostate cancers and leukemia.

The university has applied for a patent on therapy using Dr. John Bell's "very exciting" virus discovery, which leaves non-cancerous cells intact. Dr. Bell is a researcher at the cancer centre and a professor of medicine at the University of Ottawa.

Together with an American biotechnology firm, the team hopes to begin clinical trials in Canadian cancer patients in about 18 months.

The Ottawa team's research on vesicular stomatitis virus (VSV) is published in the July 1 edition of Nature Medicine, a British medical journal.

Yesterday, Dr. Bell said VSV isn't the only virus that has targeted cancer cells in lab tests. Some day, he said, patients may receive a multi-pronged cancer treatment that combines different viruses, just as chemotherapy today uses a combination of drugs.

VSV is a minor irritant that exists mainly in tropical countries, where it causes mild, flu-like symptoms. In Canada it sometimes infects cattle, causing temporary blisters on the lip like cold sores but doing no lasting damage.

Suddenly, the mild virus is showing its wild side.

"We found that every tumour cell that we infected was completely blown away by this virus very quickly, whereas normal cells were quite resistant to the virus," Dr. Bell said in an interview.

A genetic breakdown that lets a cell become cancerous appears to be the same defect that allows the VSV to infect that cell and kill it.

So far the only tests in living organisms have been done in lab mice, but they were still done on human tumours.

The researchers implanted human melanoma (skin cancer) cells into the mice. Each tumour that grew was nourished by the mouse's blood supply, while the tumour itself remained genetically human.

That means the virus treatment was knocking out human cancer cells, not mouse cancer -- an important distinction because past discoveries on mouse tumours have sometimes fizzled out when they were tried in humans.

Test-tube experiments showed the virus also destroyed breast, prostate, lung and colon cancers and leukemia, although the Bell team didn't have enough money to do these tests in mice.

The National Cancer Institute of Canada called the work "potentially very important" and "unexpected but very intriguing." It wants to evaluate experimental findings before human trials start.

The connection between cancer and the virus began when Dr. Bell was trying to identify which genes are defective in tumour cells. The search led to a gene called PKR, which controls an enzyme that carries signals inside the cell.

Tumour cells are often missing this gene, or have a damaged version of it. So they took steps geneticists often use to see what a gene does: Removing, or "knocking out," that gene from mice to see what health problems the mice will have.

They quickly learned two things: First, the mice with the missing gene were prone to cancer. Second, their cells were also prone to infection by the VSV virus.

"The penny sort of dropped there: Well, wait a second, if it (the PKR gene) isn't in the tumour cells, and we know it's very responsive to VSV, then perhaps VSV will kill tumour cells."

Tests near the end of 1998 showed the virus did indeed kill every kind of human tumour the researchers could throw at it, both in test tubes and in tumours implanted into mice.

Since that finding, the research "just rocketed ahead," Dr. Bell said. "We said, well if this is really true we're looking at a lot of kinds of tumours and this seems to be a very common feature."

They went back to research at the genetic level to see what was so special about PKR.

It turned out that some cancer cells they investigated had a normal PKR gene, but were missing other parts of the "signalling pathway" to which PKR belongs.

Together, PKR and its genetic relatives control cells' response to a natural chemical called interferon. The body produces interferon outside the cells. It binds to the surface of a cell and sends a signal to the nucleus, the command centre deep inside each cell. This signal slows down cell growth, and sometimes even makes the cell die -- key steps in preventing the uncontrolled growth of cancer cells.

But cancer cells find ways to disrupt the "pathway" from the cell's outer membrane to the nucleus, jamming the interferon signal and letting the cancer cells multiply.

But that same defect -- the loss of the interferon signalling pathway -- makes the cell vulnerable to destruction by VSV.

"Again the penny sort of dropped," Dr. Bell said. They realized that what makes a cell cancerous also makes it open to attack by the virus.

When a tumour cell sabotages the interferon pathway, he said, "it lays itself open to infection, but normally it doesn't care because it's deep inside your body and normally doesn't ever see a virus." The viral treatment worked when the virus was injected into the tumour cells.

Will medicine based on this virus be effective against cancer in humans?

"We don't know," Dr. Bell said. "This paper is just a description of our studies right now in mice, and we are excited about it and want to go on to humans, but that's the next step."

The University of Ottawa has joined a biotech company, Pro-Virus, in Maryland to take the research farther. "This company is expert at growing up pharmaceutical-grade viruses, so we can hopefully go the next step and try it in humans."

He also believes the alliance with Pro-Virus will shorten the time needed to bring the virus therapy to clinical trials.


Tom Spears The Ottawa Citizen
"http://www.ottawacitizen.com/national/000628/4356019.html"



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