Researchers from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen have developed a sophisticated method for identifying modified proteins that affect a cell's ability to repair DNA damage.

This offers hope for improving treatment options for hereditary breast and ovarian cancer using the latest type of treatments involving the so-called PARP inhibitors.

When the pharmaceutical industry develops new medicines – for example for cancer treatment – it is important to have detailed knowledge of the body’s molecular response to the medicine.

"With a better knowledge of the many complex processes which are activated in connection with illness and medication, the better the possibility of developing new drugs. We have now moved closer to targeting and treating certain cancers using the so-called PARP inhibitors – medical inhibitors used in the latest types of cancer treatment. Certain types of tumours rely heavily on PARP proteins in order to self-repair, and PARP inhibitors can be used specifically to kill cancer cells," says Michael Lund Nielsen, Associate Professor at The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The researchers have developed an advanced method for identifying the proteins which are modified with ADP-ribosylation – a biological modification affecting a cell’s ability to repair DNA damage. The research findings have just been published in the scientific journal Molecular Cell.

The forms of cancer causing most deaths among women are lung cancer, breast cancer, colon cancer, pancreatic cancer and ovarian cancer. PARP inhibitors appear to be an effective treatment for hereditary breast and ovarian cancer, but little is known about the treatment details. Our new analysis method can help shed light on precisely how the PARP inhibitor treatment is working because it can offer us more knowledge about the biological function of PARP proteins.

In the long term, it will enable us to design better and more precise PARP inhibitors, says Michael Lund Nielsen, Associate Professor at the Novo Nordisk Foundation Center for Protein Research.

DNA repair crucial for cell health

Every day, our DNA is exposed to damage which our healthy cells are capable of repairing and thus keep healthy. But the ability of certain cancer cells to repair their own DNA damage is impaired compared to standard cells and this is exploited using PARP inhibitors which block the repair systems of cancer cells.  In principle, PARP inhibitors both damage healthy and cancer cells, but normal cells have different survival mechanisms in comparison to cancer cells. PARP inhibitors therefore appear to offer new and much improved cancer treatment options.

Treatment with PARP inhibitors

PARP treatment is a new and individualised type of cancer treatment. It is a so-called targeted treatment which exploits a weakness inherent in cancer cells. PARP inhibitors have yet to be marketed, but many companies are testing them in clinical (phase 1-3) trials. So far, the PARP inhibitors are only available for experimental purposes.

"Our analysis method makes it possible to map the movement of PARP inhibitors, opening up possibilities for the optimised treatment of breast and ovarian cancers with fewer side effects. It is also being examined whether PARP inhibitors can be used in combination with chemotherapy and/or radiation therapy in connection with other cancers. In particular, radiation therapy produces many unpleasant side effects, but there are indications that optimised treatment could be achieved by combining radiation therapy with PARP inhibitors, as PARP inhibitors make cancer cells more susceptible to radiation therapy," says Michael Lund Nielsen.

Using radiation and chemical compounds, the researchers started by damaging the DNA in cells. They then isolated proteins modified with the ADP-ribosylation and identified them using mass spectrometry, a technique making it possible to determine a protein’s identity and the sites where the ADP-ribosylation chemical changes occur.

Source: University of Copenhagen