Clare Jonas
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Repairing the rope: how PARP inhibitors stop cancer

Clare Jonas
Posted by
Updated 06 Aug 2018

A protein called PARP1 can cause a build-up of DNA errors in some types of cancer. There are drugs that can stop PARP1 from wreaking havoc in cells – but how do they do it? Professor Tatjana Stankovic has the answer…

Think of your DNA like a rope, made of two strands of molecules twisted around each other
Think of your DNA like a rope, made of two strands of molecules twisted around each other

Every time your body makes a new cell, it has to make a full copy of the DNA in an existing cell to be transferred to a new one. Inevitably, DNA gets damaged in the process of making a new cell. DNA is a molecule made up of two strands, so it’s possible to damage one of the strands – think of it like a rope fraying – or both of the strands, like a rope breaking. If the breaks don’t get repaired, then the cell is likely to die. While this is not good news for the cell, it is good news for our overall health, because cells with damaged DNA not only can’t do their jobs properly, but they can also be dangerous and lead to cancer.

Of course, it’s risky, and a waste of time and energy to make a cell that has damaged DNA, so our cells have proteins that can repair damage. Some of these proteins can repair two-strand breaks, and some can only repair one-strand breaks. The two-strand repair proteins are particularly useful because they never make errors in their repairs: the ‘rope’ of DNA is as good as new once it’s done. Unfortunately, the repair proteins are also coded by DNA, which means that they too can be damaged.

DNA damage might mean that not enough of the repair protein is made, which is what happens to the BRCA family of two-strand repair proteins in some types of breast cancer. In this case, a one-strand repair protein called PARP1 might take over the job and recruit other proteins to help, but unlike BRCA proteins, they cannot perform a perfect job and delete some DNA on either side of the break. It’s as if the rope of DNA has been repaired by knotting two ends together, so it’s now shorter than you need it to be.

Damage might also mean making too much of a repair protein. This is what happens with PARP1 in several different kinds of cancer including some non-Hodgkin lymphomas – also causing errors to build up in the DNA. So how do we solve this problem?

Getting rid of PARP1

In the last five years, a new wave of cancer drugs has arrived. These are called PARP inhibitors, and as the name suggests, they stop PARP repair proteins from working. In cancers where there’s too little BRCA, the drugs prevent DNA repair from happening at all – the rope breaks, which kills off the cancer cells. In cancers where there’s too much PARP1, they reduce the amount of PARP1 and allow other DNA repair proteins like BRCA to do their job so that the cell can carry on its business. In all kinds of cancers, they only affect cells with an imbalance in the DNA repair proteins, since healthy cells can use other DNA repair mechanisms. Because many currently-available treatments like chemotherapy damage healthy and cancerous cells alike, PARP inhibitors are a real breath of fresh air in cancer medicine.

PARP inhibitors also have a second action: they trap the PARP repair protein at damaged parts of the DNA, as though a stone is caught in the strands as the rope is made. Normally PARP is released once it’s done its job so that it can do repairs elsewhere, but when it’s trapped it can prevent the cell from making a copy of the DNA. This disrupts the cycle of creating new cells with damaged DNA, preventing the cancer from growing.

But until now, no-one has been sure where exactly the PARP inhibitors are likely to be trapped. This is where Professor Tatjana Stankovic, a Bloodwise-funded researcher at the University of Birmingham, comes in.

Professor Tatjana StankovicProfessor Tatjana Stankovic

 

Can PARP inhibitors be used in other kinds of cancer?

“Our research team in Birmingham has been working for many years on understanding how we can manipulate faulty DNA repair in cancer cells to specifically kill cancer cells, while sparing healthy cells,” Professor Stankovic says. “To do this, we need to learn how cancer cells survive with faulty DNA repair mechanisms and which back-up proteins they use if one DNA repair protein is faulty.”

Professor Stankovic and her collaborators elsewhere in the UK, Canada and the USA used three different kinds of cell to carry out their experiments: breast cancer cells, cervical cancer cells, and healthy cells. They then used a gene-editing technique called CRISPR to remove individual genes in each cell before treating them with olaparib, a PARP inhibitor. Since cells with properly functioning DNA damage repair mechanisms would not die as a result of olaparib, this allowed them to find out whether changes to an individual gene would alter DNA damage repair to the extent that olaparib could kill the cell off – this is called ‘sensitizing’ the cell to olaparib.

Dr Angelo Agathanggelou, one of the researchers on this project, at work in the labDr Angelo Agathanggelou, one of the researchers on this project, at work in the lab

In total, the researchers found 73 genes that, when damaged or removed, would sensitize a cell to olaparib. While most of these genes were directly related to DNA damage repair, there were a small group that were related to other tasks. Three of these genes were related to a protein complex called RNase H2. RNase H2 is faulty in cells with some forms of blood cancer, including multiple myeloma, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia. This is a very promising finding as it suggests that PARP inhibitors could be used to treat some patients with these blood cancers. Because damaged DNA repair is typically a feature of aggressive cancers, this is particularly exciting news for people with hard-to-treat disease who have exhausted currently available options – and this isn’t restricted to blood cancer.

Professor Stankovic explains: “Importantly, our findings are applicable to a range of cancers, including some aggressive prostate cancers that have spread to other parts of the body, bladder cancers, sarcomas (cancers of the connective tissues) and others also have defective RNase H2. All these cancers might therefore respond to PARP inhibitors, a promising new targeted drug with few side effects.”

You can read more about Professor Stankovic’s research in Nature.

 

Research at Bloodwise                                 

The research in this blog is part of Professor Stankovic’s Bloodwise-funded research on developing new treatments for chronic lymphocytic leukaemia.

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