Canadian researchers believe they have solved a puzzle that has long baffled doctors — why no chemotherapy drug has been found that can treat a type of brain tumour that primarily affects babies and toddlers.
Their discovery has led them to an FDA-approved drug that may help eradicate a tumour known as an ependymoma, the third most common brain cancer diagnosed in children.
"It's a very slow-growing tumour, and the current treatment in 2014 is surgery and radiation," said Dr. Michael Taylor, a pediatric neurosurgeon at Toronto's Hospital for Sick Children who led the research reported Wednesday in the journal Nature.
"We don't give chemotherapy because the numerous clinical trials that have been done using every chemotherapy known, none of them work."
Despite surgical and radiation treatment, about 60 to 70 per cent of babies with an ependymoma don't survive, usually because the tumour recurs, he said, noting that the peak age of diagnosis is about nine months.
"They can't even walk yet and they're dying of brain cancer."
Frustrated by that missing weapon in their treatment arsenal — most cancers are attacked with a triad of surgery, radiation and chemotherapy — the Sick Kids researchers decided to look at the genetic makeup of patients' tumours.
By sequencing the DNA of 47 tumour samples, they discovered that ependymomas are unlike other cancers: they don't contain the genetic mutations that are the typical hallmark of cancer.
"If you think of the DNA as a three-billion letter book in every cell and it's sort of the code of instructions for a cell on how to behave, mutations are things like misspelled words, words that are deleted or added, or book chapters that are out of order," Taylor explained.
"In ependymoma's book, everything is spelled right and everything's in the correct order, but the font is all messed up. It's all written in the wrong font."
He said the font — or how the DNA is packaged — appears to be similar to what would be seen in embryonic stem cells, which have the ability to continuously divide and give rise to other cell types.
"We think that these are neural stem cells that have a Peter Pan syndrome — they never got the message to grow up, and just keep growing and growing."
Most chemotherapy drugs work by promoting damage to DNA, causing cancer cells with mutated genomes to self-destruct. "Since ependymomas don't have significant mutations, it explains why chemotherapy has not worked," Taylor said.
"For most cancers, there's been targeted therapies or experimental things. For ependymoma, until a week ago, there was nothing. It was off to Mexico for avocado pits and shark cartilage."
Dr. Peter Dirks, a neurosurgeon and stem cell scientist, said the team is the first to grow patients' ependymoma cells in the lab, allowing the researchers to perform the DNA sequencing.
"And that really enabled the next phase of the project to go forward, to see whether targeting this abnormal packaging signal would show any effectiveness or be a promising strategy for treatment of these tumours," said Dirks, whose lab discovered the existence of brain cancer stem cells in 2003.
The team then began testing existing drugs on the tumour cells grown in the lab. One of them — a medication called decitabine that is FDA-approved to treat a bone marrow cancer — was found to work against the tumour cells.
They then tested it directly on an ependymoma tumour that had been removed from a young patient, and its effect was again positive. The boy, who was not identified for privacy reasons and is "very, very sick," is currently being treated with decitabine, sold under the brand name Dacogen.
Taylor would only say the boy has reportedly "improved clinically."
Even such preliminary results have given hope to Liz Gavin Kerr, in case her daughter Isla's ependymoma should recur.
The three-year-old Toronto girl is in remission after being treated with surgery and radiation for a tumour diagnosed when she was 18 months old.
Kerr said her physically active toddler had begun having episodes of severe vomiting and was having slight balance problems that lasted for a couple of days. Doctors thought she had a stomach bug, and when she recovered that seemed to be the case.
But after being well for two months, the vomiting suddenly began again, her mother recalled. "Then her mental state started to decline. She started to become more clingy and didn't want to play as much."
A CT scan turned up a walnut-sized tumour in her brain. Within 12 hours, Isla was in surgery at Sick Kids to have the tumour removed. That was followed by almost seven weeks of radiation, a treatment that can later lead to cognitive and physical deficits.
"We always say that we are the unluckiest, but also the luckiest people because these kids can come out with some really serious side-effects from the brain surgery," said Kerr.
After the operation, Isla could not walk or even crawl, but she is now back to running around with her two older brothers.
"She is doing amazing," said Kerr. "She really is the same as every other three-year-old. She is happy, doing everything that everyone else is doing and there's absolutely no physical deficits so far."
Despite living daily with the fear that Isla's tumour might come back, Kerr is excited about the prospect of a drug that might help her daughter if that happens.
"For our family, of course, we hope that it never comes back. But in combination with that, we hope that as a result of this research that ... it would be great if this were the drug that went forth and cured all ependymomas."
While elated about the team's discovery, Taylor said only properly conducted clinical trials of children with an ependymoma can decide whether decitabine would be an effective chemotherapy, and that will need about $2 million in funding even for an initial study of 15 to 20 patients.
"We need a very well-heeled and generous Canadian donor or a public-spirited Canadian company to set up and give us the money so we can run this clinical trial here in Canada," said Taylor with no apology for the funding pitch, noting that the drug is "very expensive."
"This is the first real target for ependymoma," he said. "Now we have something for these really unfortunate families who have their babies literally taken out of their arms."