Putting the brakes on cancer


IT SEEMS LIKE the perfect combination – a substance that kills cancer cells while sparing healthy cells, writes Claire O’Connell in today’s Irish Times.

Not only that, the biochemical in question is involved in normal cell growth. Researchers at NUI Galway are looking at the protein and how, if they block its action, it sends growing tumour cells to the gallows while, crucially, healthy cells stop growing but stay alive.

The key protein, called CDC7 kinase, is a “cell cycle” regulator and appears to be involved in copying DNA, which cells need to do before dividing and increasing their number, says Corrado Santocanale, professor of molecular medicine at NUIG. Before moving to Galway, he worked at pharmaceutical company Nerviano Medical Sciences in Milan, developing a drug to block CDC7 kinase in the hope of stopping tumour growth. They found that the drug had different effects on normal and tumour cells.

“There are two concepts here: first, we stop the cell from dividing, we stop the growth, and the second, very important, concept is how the same cells that are forced to stop then react. They can either stop dividing and stay alive, or they decide that they can’t stay in that condition and therefore die and get eliminated,” explains Santocanale.

“What we found previously is that by blocking the CDC7 kinase, we are seeing two very different things in normal and cancer cells. Normal proliferating cells were stopping growing and remaining alive, while cancer cells just couldn’t stand it so they died.”

The observation led to a new anti-cancer compound that blocks CDC7 kinase, which is being approved by the US FDA for clinical trials, explains Santocanale. “This drug, in theory, has the potential to treat every type of cancer,” he says. “We expect it will have an effect against proliferating cells, and in the body most of the cells are not proliferating, but there are some compartments that are. If the compound doesn’t kill those normal cells and only kills the tumour cells, then, when the drug is eliminated from the body, the normal cells will recover and the tumour cells will not be able to.”

But key questions still remain, including the most basic: why do the cancer cells die and the normal cells survive?

“That’s the observation, and one of the things we are doing now is trying to understand why this is occurring,” says Santocanale, whose research is funded by Science Foundation Ireland, Cancer Research Ireland and Molecular Medicine Ireland.

He describes how his lab is going “back to the basic biology” of cancer cells and the kinase to look for clues that could help identify patients who would benefit from blocking CDC7 kinase.

One approach is to better understand how the kinase itself is regulated within the cell by “microRNAs” that put the brakes on proteins, explains Dr Laura Barkley-Elliman.

“MicroRNAs have only been discovered in the last 10 years, they are small RNA molecules and they actually down-regulate the protein,” she says. “And a lot of people have shown that in cancer cells there is aberrant microRNA expression.”

Barkley-Elliman, a Cancer Research Ireland fellow at the National Centre for Biomedical Engineering Science in NUIG, is now looking at four key microRNAs that affect CDC7 kinase.

At the moment, her work is on cells derived from ovarian cancer, but it is important to look at non-cancerous cells too, she explains. “My aim is also to look in normal cells to see how it is being regulated and to see if there’s a difference between the normal cell and the ovarian.”

By better understanding how the system works, the hope is to find a way to identify cancer patients who may respond well to the kinase being blocked.

“I think it will be a long way down the road that microRNAs will be used as therapies, in combination therapies or even to identify patients that would respond to this treatment, this CDC7 inhibitor,” says Barkley-Elliman, but she believes the approach offers potential.

“You could stratify patients into responders and non-responders by looking at the microRNA expression, like a biomarker.”