Understanding Cancer’s Unique Advantage

David Litchfield, PhD’87, believes the key to fighting cancer is finding out exactly why it is that cancer cells refuse to die.

By studying the complex network of signals and transmission of information between cells, Litchfield, a professor and chair in the Department of Biochemistry at Schulich Medicine & Dentistry and his team are aiming to pinpoint why and how cancer cells are able to adapt in ways that allow them to survive when normal cells under the same circumstances would die.

“The ability of cells to adapt is what maintains our health. We can adapt to our environment, and our nutritional state, so our survival and our good health is a consequence of our adaptability,” said Litchfield. “Cancer cells acquire exceptional adaptability giving them a unique advantage.”

This adaptability, it turns out, is what makes designing cancer therapies so difficult.

Litchfield’s lab is looking specifically at the role of protein kinases of which there are 500 coded in the human genome, with an estimated 200 to 300 expressed in any individual cell. The promise of protein kinases as therapeutic targets was revealed in 2000, when a drug called Gleevec was approved for use in North America to treat a specific form of leukemia. The drug, which targets the protein kinase BCR-Abl has proven to be highly effective. It is so effective in fact, that there are currently an estimated 100,000 leukemia patients around the world living productive active lives because of it.

The thing that’s striking about Gleevec is that while there are some patients who do acquire resistance, it has proven to be extremely durable. Now, the goal is to find other therapies that work just a well.

This, says Litchfield, is the challenge.

Researchers have been successful in targeting other protein kinases in specific pathways to block cancer cells from proliferating, but Litchfield says that these drugs often work really well for a only a few weeks and then they suddenly stop working. The cancer cells, then, come back even more aggressively than before.

Litchfield described how this can happen because protein kinases are organized into complex networks so that when one is protein kinase is blocked, the cell can use different protein kinases within the networks to get around the blockage.

“This is why instead of looking at individual targets, you really need to look at the entire network,” Litchfield said, likening it to a football game. “If you are keyed on the fullback only, as soon as he pitches the ball, you have a whole new problem.”

Considering the size of the protein kinase family with its 500 members, “So that’s a pretty big football team,” Litchfield said.

Using various techniques, including proteomics and biosensors to watch what is happening in live cells, Litchfield and his team are aiming to anticipate how this complex network is going to adapt. This will enable them to key in on not only the primary target, but also any additional pathways that enable cancer cells to acquire resistance to the initial treatment.

Litchfield calls this approach “precision medicine.” Because cancer isn’t just one disease, the idea is that by understanding the underlying molecular defects of each unique disease researchers can match the intervention to those defects.

“If we can understand the network adaptations that are unique to each individual form of disease, this will lead to combination therapies that shut down the entire network of pathways,” said Litchfield. “Although you are hearing this from an eternal optimist.”

And it’s that eternal optimism that keeps Litchfield engaged in this work. The advances he has seen in understanding cancer over the past two decades give him hope they will be able to find ways to stop it.

“Much of what we are doing now was unimaginable when I first started doing research two and a half decades ago,” he said. “It seems that every day there is more to learn than there was the day before.”