The DNA is every cell of the body is constantly getting damaged and it is constantly getting repaired too by the cells' DNA repair system to keep it functioning well. There are times when the repair processes go wrong which marks the beginning of cancer. But, the surprising part is that these repair processes can be exploited to treat the disease.
For years, DNA repair mechanism has been the key focus for formulating cancer treatments. Courtesy that, today we have a new family of cancer drugs called PARP inhibitors. They exploit a weakness in cancer cells that already have faulty repair toolkits like, cancers caused due to mistakes in the BCRA1 or 2 genes, which are crucial for DNA repair.
An important role was played by scientists from Cancer Research UK in the early development of PARP inhibitors. And the first of them, olaparib (Lynparza), is licensed for use within the EU for women with a certain type of ovarian cancer.
Our experts in the field, Professor Laurence Pearl, at the University of Sussex and his colleague (and wife) Dr. Frances Pearl, a computational biologist, are working further to discover new therapies and treatments.
Laurence explains that mistakes in our DNA can have disastrous consequences and hence, our cells have evolved a lot in their ways of repairing it. Still mistakes happen and it’s really important that cells protect their DNA and fix any damage as matter of priority. Our cells are equipped with a team of repair systems, known collectively as the DNA damage response – they work hard to keep things running smoothly. There are repair cells with different level of expertise to work on the most basic DNA repair job to rectify major faults. When repair work is on, essential functions in the cell will halt, like metabolism will slow down and cells will stop dividing. Small mistakes can be fixed quite easily, but too many mistakes are usually too bad to fix. In such an eventuality, the only solution is to admit defeat: the cell activates a self-destruct programme known as apoptosis.
Frances explains that all cancer cells have genetic mistakes or abnormalities which drive their growth. To carry on growing quickly they need to turn off some of their DNA checking and repair tools to tolerate these mistakes. The loss of this DNA ‘proofreading’ allows more mistakes to creep in, fueling more genetic chaos and driving tumour evolution. The surprising thing is, it is quite common for cancer cells to disable some of their molecular mechanics and it is quite frequent.
Understanding different molecular mechanics and the decision-making involved in repairing DNA can help in identifying new drug targets. By disabling the team members that check DNA is repaired properly, cancer cells are treading a fine line. If they get rid of too many of these cells and completely lose the ability to fix DNA, it can get very disorganized and the cell dies. This is something the researchers can take advantage and push cancer over the edge.
Traditional drug design is based on finding overactive molecules that are driving cancer, then blocking their activity but what Laurence and team are focusing on – is how to overcome the effects of molecules that are missing so to say how to design drugs that inhibits the functions on which the cancer cells runs.
According to Laurence, there are two really promising avenues to try, to turn the idea into new therapies for patients. One is – cancer patients’ tumours can have faults in different parts of their DNA repair toolkits. If it can be figured out, exactly which DNA repair genes are faulty in a particular cancer, work can be done to figure out what type of damage it can’t fix. The second approach is developing drugs that take away parts of the cell which the cancer needs to survive.
Combining these two approaches might be even more successful. It has the potential to overcome cancers that have become resistant to chemotherapy. It’s clear that the DNA damage response is an area of weakness in cancer cells. It will be fascinating to see how further developments are made in this area.