Investigating a gene that produces cancer-fighting protiens

Robert Korneluk has a vision of where he would like to be in 10 years' time. It's on a golf course where he has just shanked a shot and turns to his golf mates and oh-so-casually utters, "Oh, well, I might not play golf so well but at least I helped develop therapies to treat cancer."

Sure, it's a joke. But it's definitely not an impossible vision.

In 1995 Korneluk, a researcher at the Children's Hospital of Eastern Ontario (CHEO), and colleague Alex MacKenzie discovered a gene producing a protein associated with programmed cell death - scientifically called apoptosis. Initial findings also showed that a version of the protein seemed to be effective in helping combat cancer.

Aegera Therapeutics Inc., a Montreal-based company, commercialized these findings and signed a deal with the U.S. biotech giant Human Genome Sciences that could be worth as much as $315 million.

So why is apoptosis so exciting to both cancer researchers and drug companies?

As Korneluk, who is now director of the Apoptosis Research Centre (ARC) at CHEO, points out, a central problem in treating cancer - maybe even the central problem - is the cancer cells' apparent pact with deathlessness. "The genes in cancer cells are almost bulletproof when it comes to dying, and that is probably why cancer is so resistant to chemotherapy and radiation and other harsh treatments," Korneluk says.

What seems to happen is that the cancer cells are primed by proteins that inhibit apoptosis (IAPs) - the compounds that make cancers much harder to kill than the healthy cells around them. As a result, biochemically armoured cancer cells are able to survive chemotherapy at dosages that are highly lethal to ordinary cells.

The first-order approaches that have grown out of the hospital's initial findings have been drugs that reduce the cancer cell's chemical armour against apoptosis. At the very least, it is hoped that the removal of cancer's defenses will allow today's cancer chemotherapy treatments to be less harmful to people taking them. "Drugs that are in clinical trials suggest that maybe you can use one-tenth as much chemotherapy as is now used and still kill off cancer cells," says Korneluk.

But fighting cancer is not the sole application for the apoptosis compounds. If Korneluk was looking for something different to brag about on the golf course, it might well be the bulking-up of IAPs in non-cancer cells. Specifically, Korneluk and MacKenzie's original research aimed to find the genetic defect that leads to spinal muscular atrophy. They now believe that what happens in many neurodegenerative diseases - such as muscular dystrophy, glaucoma or Alzheimer's - is that genetic mutations stress normal cells and cause them to die off early.

"So what we want to do now is increase these cells' resistance to death," says Korneluk.

This application has also caught the drug company's attention. In September of 2008, Aegera announced it had licensed an IAP protein that the Ottawa group had developed to the U.S. company Neurologix. The company was going to use the protein for the potential treatment or prevention of Huntington's disease. In tests using mice with Huntington's-like conditions, Neurologix found IAP gene therapy slowed the progress of the disease.

As you might expect, Aegera is delighted with where the research has taken it. "Our understanding of apoptosis, developed through licensing arrangements and close collaboration with ARC, has permitted us to position Aegera Therapeutics as a global leader," says a proud Donald Olds, Aegera's chief operating officer.

And what about Korneluk? The ever-fanciful man sees not just golf courses but Pablum in his and his institute's future.

"Our relationship with Aegera could be our Pablum," he opines, referring to the then revolutionary infant formula invented at Toronto's Sick Children's Hospital during the 1920s. Revenues from this innovation supported research endeavours at the hospital for decades.

Because of the royalties that have already started flowing from the IAP patents, "Apoptosis could end up funding our institute well into the future," says Korneluk.