In Denmark, cancer is the most frequent cause of death, and one of the most effective ways of fighting the disease is radiotherapy.

Just over 362,000 Danes have been diagnosed with cancer, and eventually, half of them will need radiotherapy.

Radiotherapy is not perfect, though, as cancer cells can develop resistance to the treatment.

Eventually, this means that cancer patients risk dying because the treatment is ineffective.

But now researchers from the University of Copenhagen have discovered that an enzyme called Caspase-activated DNase (CAD) plays a key role in cancer cells’ response to radiotherapy.

“We have learned that CAD helps cancer cells circumvent radiotherapy, which means that it can continue to grow. When we remove CAD from the cancer cells, the effect of radiotherapy increases significantly,” says Associate Professor Claus Storgaard Sørensen from the Biotech Research & Innovation Centre (BRIC) and adds:

“We hope our discovery can pave the way for the design of drugs capable of inhibiting CAD, increasing the effect of radiotherapy and other types of cancer treatment.”

CAD tells cancer cells to delay division

Normally, CAD is part of our immune system, where the enzyme helps tidy up the cells.

“CAD is known to promote cell death, for example when a cell is infected with virus.

This process is known as apoptosis and it is a perfectly normal part of the healthy body.

But surprisingly, when it comes to cancer cells, we find that the opposite is the case.

Here the enzyme helps ensure the survival of the cell,” explains Claus Storgaard Sørensen.

When cancer cells are exposed to radiotherapy, the chromosomes are severely damaged.

This puts the cancer cells under time pressure, as they have to repair the chromosomes before they can continue to grow. It is in this process that the cancer cells exploit CAD for their own unique purpose.

The CAD enzyme generates limited damage to DNA.

The cancer cells recognise the limited damage as a stop signal to avoid cell growth when the chromosomes are severely damaged by radiation. 

 "CAD gives the cancer cells a stop-growth signal. CAD does so by causing its own unique and limited damage to the DNA, which the cancer cells recognise as a stop-growth signal. Once this stop-growth signal happens, the cancer cell uses this opportunity to repair the entire broken DNA and restart its growth. Essentially, the cancer cell uses a controlled form of DNA damage to bypass and repair the damage caused by radiation," says Claus Storgaard Sørensen and adds:

”But if you remove CAD, the cancer cells lose the defence mechanism that gives them time to repair the chromosomes. The cancer cells will thus attempt to divide despite suffering from significant chromosomal damages induced by radiotherapy, which will lead to their demise. Hence, inhibiting CAD will increase the effect of radiotherapy.”

Easier to distinguish cancer cells from healthy cells

Aside from the discovery’s contribution to more effective radiotherapy, Claus Storgaard Sørensen and his colleagues hope it will make it easier to target cancer cells and thus protect the normal cells.

“CAD only tells cancer cells to delay division after radiotherapy; this does not happen to healthy cells, which are not regulated by CAD. Therefore, because we know that we are able to inhibit CAD, our discovery can help us target cancer cells exclusively. The ongoing development of CAD inhibitors is expected to result in more precise treatment, reducing the amount of side effects of radiotherapy,” says Claus Storgaard Sørensen.

What the researchers have done

The researchers have studied the connection between CAD and effective radiotherapy in human cells in the laboratory and in mice.

They have conducted in vitro studies to determine what happens to human cells with and without the CAD enzyme, respectively, when exposed to radiotherapy.

This research showed that radiotherapy is more effective in cells without CAD.

The researchers reached the same results in tests on mice.

Potential side effects of radiotherapy include damaged tissue and nerve damage in the areas subjected to radiotherapy.

The researchers behind the new study have already developed a treatment method inhibiting CAD, the effect of which has been proven in simple laboratory tests.

But the road to actual drugs inhibiting CAD in people subjected to radiotherapy is long.

“I hope that we will see the first tests on humans within five years. But first we need the pharmaceutical companies to get involved.”

Source: University of Copenhagen - The Faculty of Health and Medical Sciences