Discovery may make cancer cells more vulnerable to radiation therapy

Disease and treatment 26. jun 2022 3 min Associate Professor Claus Storgaard Sørensen Written by Kristian Sjøgren

Researchers have identified an enzyme that cancer cells use to defend themselves against radiation therapy. According to a researcher, inhibiting the enzyme with drugs could increase the effectiveness of radiation therapy and thereby kill cancer cells more efficiently.

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About 50% of all people with cancer undergo radiation therapy, but this is not always very effective. The reason is that radiation therapy has a narrow therapeutic window between killing the cancer cells and not harming healthy cells.

Cancer cells have a built-in mechanism to mitigate the effects of radiation therapy, and researchers have now identified this.

The new knowledge could enable doctors in the future to eliminate the cancer cells’ defences against radiation therapy, thereby widening the therapeutic window.

“Normal cells and cancer cells differ, and these differences are not sufficiently exploited. Thus, there are considerable perspectives for including drug treatment in radiation therapy. Our discovery could enable cancer cells to become more vulnerable to radiation therapy without increasing the damage to healthy tissue,” explains a researcher behind the study, Claus Storgaard Sørensen, Associate Professor, Biotech Research & Innovation Centre (BRIC), University of Copenhagen.

The research has been published in Science.

How cancer cells and healthy cells differ

The researchers initially carried out various types of genetic screening to identify functional differences between healthy cells and cancer cells and to discover how various factors differentially influence the response of cancer cells and healthy cells to radiation therapy.

Radiation therapy often fails because the cancer cells deploy an arsenal of mechanisms to mitigate the effects of radiation-induced damage to their DNA, since the radiation would otherwise destroy the cancer cells.

In the screening, the researchers discovered two factors that influence how cancer cells respond to radiation therapy.

One previously known factor, the ability to repair DNA damage, ensures that the cancer cells avoid major damage to the genome and is difficult to inhibit with drugs.

The second factor involves the enzyme caspase-activated DNase (CAD), and research shows that it plays a new role by helping cancer cells defend themselves against radiation therapy.

“CAD is usually involved in the immune system and in killing diseased cells. In this case, CAD actually protects cells from being killed, but unfortunately the protected cells are the cancer cells that we want to kill,” says Claus Storgaard Sørensen.

Cancer cells use CAD to defend against radiation therapy

Normal cells possess several protective mechanisms against radiation damage by constantly ensuring that the damage to the DNA is repaired.

Most of these mechanisms are deactivated in cancer cells because they simultaneously inhibit growth, and cancer cells must grow uninhibitedly. The loss of the various options for efficiently repairing DNA also makes cancer cells more vulnerable to radiation therapy than normal cells.

The new study reveals that, although CAD does not play a very major role in defending normal cells against radiation therapy, it is crucial in defending cancer cells.

Claus Storgaard Sørensen explains that CAD carries out some small and simple DNA breaks in connection with radiation therapy that signal to the cancer cells that they need to stop dividing. These simple and easily repaired lesions ensure more time to repair the major damage caused by the radiation.

At some point, once the radiation damage has been repaired, the activity of the CAD dwindles, and then the cancer cells can divide again.

“Activating CAD is like gently applying the brakes to cell division. Cancer cells that try to divide after major radiation damage fail and die. But by gently applying the brakes, the cancer cells can repair the radiation damage before continuing to divide. This is why radiation therapy sometimes fails,” explains Claus Storgaard Sørensen.

Lack of CAD boosts the effectiveness of radiation therapy

The researchers also examined what happens when CAD is removed from cancer cells and healthy cells. The cancer cells without CAD were much more vulnerable to radiation therapy. However, healthy cells were not affected to the same degree when CAD was disabled.

“The only role of CAD in cancer cells is regulating cell division after radiation. This difference between the two cell types may be useful in therapy,” says Claus Storgaard Sørensen.

Potential for developing new types of therapy

Based on their discovery, the researchers are now developing CAD-inhibiting drugs that can be given to people with cancer undergoing radiation therapy, thereby eliminating the cancer cells’ defences.

The researchers from the University of Copenhagen have already developed novel candidate drugs that work as intended and the goal is to find partners who can help to develop them further.

“We think that this type of supplemental therapy will bolster radiation therapy for many types of cancer, including bowel cancer, breast cancer or brain cancer. Acquired resistance to radiation therapy is aided by the presence of the CAD defence mechanism, and we want to remove this option for the cancer cells,” concludes Claus Storgaard Sørensen.

Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress” has been published in Science. In 2019, the Novo Nordisk Foundation awarded a grant to Claus Storgaard Sørensen for the project Novel Compound-based Sensitisation Approach to Radiation Therapy.

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