Attacking the ALT pathway

Posted: 08th September 2021

“The problem of chemotherapy – experienced by most cancer patients – is that while it kills cancer cells, it also kills useful cells in many parts of the body. Hence the terrible side-effects, like hair loss,” explains Associate Professor Andrew Deans, Head of SVI’s Genome Stability Lab.

Cancer arises through cell replication gone mad.

“Our cells are continually dividing and reproducing themselves – that is how children grow taller and adults continue to grow hair, nails and skin,” Andrew notes. “But cancer hijacks this process, to replicate cells that no longer respond to the usual, healthy processes of cellular growth and death.”

Understanding what drives this crazed cell behaviour and how we can ultimately control or contain it is a key focus of Andrew’s research.

First identified in 1938, telomeres are tiny caps on the ends of each of our chromosomes. They function as a molecular clock, wearing down each time the cell divides and reproduces itself. But cancer cells have developed clever ways to avoid the telomere’s usual limiting of cell life. One of these death-defying processes is called “alternative lengthening of telomeres”, or ALT, which borrows long telomeres from other parts of our DNA and copy/pastes them onto the cancer cell’s shortening ones.

“It’s an ingenious adaptation that keeps the cancer cells going, when they should naturally die,” says Andrew.

This ALT pathway is considered a strong potential target for new cancer therapies.

“The beauty of developing treatments based on the ALT pathway is that there would be considerably fewer side effects, because normal cells would be unaffected,” says Andrew. “This is a cancer-specific mechanism that we can harness to kill off cancer cells. That makes it a very attractive prospect for research aimed at developing new-generation cancer treatments.”

ALT-driven tumours exist across the spectrum of cancer, but for specific cancer types they can represent a third or even half of patient cases.

“For instance, sarcoma, a tumour cancer that forms in soft tissues like blood vessels, muscles or nerves: 30 to 50 per cent of these cancers are typically ALT,” Andrew comments.

“If we can work out how to attack the cancer’s ALT pathway, it will be a double victory, because these cells’ ability to endlessly replicate makes them much more resistant to treatment. Sadly, patients with sarcoma and other high-load ALT cancers have much poorer outcomes.”

“Research on ALT cells has a good chance of yielding drug treatments within the next decade,” Andrew concludes. “That’s what keeps me and my team going, every day.”

For more on the lived experience of cancer, read the story of a cancer survivor.

IMAGE: Chromosomes under the microscope

For more information please see: Genome stability