A ‘lethal weapon’ in the search for new cancer treatments?

Cancer Research UK-funded scientists working on an experimental treatment, initially thought to be helpful for only a minority of patients, have found evidence that it might be able to benefit many more people than first thought.

Although their name suggests an indigestion remedy rather than a chemotherapy, PARP inhibitors are part of a new generation of cancer drugs – and Cancer Research UK has been working on bringing them to the clinic for over a decade.

These drugs are highly targeted to people whose cancers are due to specific genetic faults. Early trial results suggest they can be very effective. But could they work on cancers with other genetic errors?

So what’s a PARP inhibitor?

PARP inhibitors were developed by exploiting detailed knowledge of what happens when a certain enzyme – Poly-ADP-Ribose Phosphorylase (PARP) – is blocked in cancer cells.

PARP is a key player in a cell’s DNA repair machinery (we’ll look at some others later). Its normal role is to repair tiny nicks in the DNA helix –the little snags and tears that occur during the day-to-day life of a cell. Although a little DNA damage is a bad thing – it can lead to cancer – a lot of it triggers another defence mechanism – cell suicide or apoptosis.

Armed with this knowledge, scientists have been working to turn it into a cancer treatment.

Probably the first person to figure out how to use cancer cell’s own repair mechanisms against them was Cancer Research UK-funded scientist Professor Steve Jackson in Cambridge.

He figured that if you found cancers that had already got loads of errors in them – cancers in which other parts of the DNA repair system had already gone wrong – and blocked PARP in these cells, it could tip them over the edge, triggering suicide mechanisms in the cancers cells, and forming an effective treatment. Over the years he and his team, including scientists at a company we helped him set up called KuDOS, have been discovering and developing potential drugs to block PARP and other molecules involved in DNA repair.

Luckily, some of the cancers caused by defective DNA repair are well known and understood. These include the infamous BRCA ‘hereditary’ cancers, which make up a minority of breast, prostate and ovarian cancers.

BRCA and PARP – the belt and braces of DNA repair

BRCA1 and BRCA2 are two other components of our cells’ DNA repair systems. People who inherit a fault (mutation) in a copy of one of their BRCA1 or BRCA2 genes are highly likely to get breast, ovarian and prostate cancer at some stage in their lives. This is because as their cells divide, they pick up random errors that can’t be repaired by the proteins produced by the BRCA genes.

But their cells still produce PARP – so the DNA damage can’t ever get above the ‘critical’ level needed to trigger a cell’s anti-cancer suicide mechanisms.

This highlights the fact that normally, PARP and the BRCA genes act together as the cell’s ‘belt and braces’, ensuring that breaks in the DNA ladders in our cells are detected and repaired – protecting us from cancer-causing damage.

Chemotherapy – using DNA damage to treat cancer

Many chemotherapy drugs work by directly damaging DNA in cells – especially cancer cells. But they don’t always work, and over a decade of research has gone a long way towards revealing why.

It seems that cancer cells are highly effective at producing PARP – so they can repair the damage inflicted on them by chemotherapy drugs. And so blocking PARP whilst smashing cancer’s DNA to bits with powerful chemotherapy drugs seems like a sensible way to try to overcome cancer’s defences.

But where to start?

Well, what about patients who already have defective DNA repair due to faults in their BRCA genes? Blocking PARP in cancer cells with no ‘back-up’ mechanism should be a hugely effective way to treat cancer.

This is exactly what is being tested in a small number of clinical trials across the country, including this PARP inhibitor trial funded by Cancer Research UK.

But BRCA mutations only account for a fraction of cases of cancer – for example, fewer than one in twenty breast cancers is linked to a BRCA fault. Could these drugs be used to help a larger number of patients?

The lethal weapon

To find out, Alan Ashworth and his team at The Institute of Cancer Research carried out an experiment known as a synthetic lethal screen. The results of the experiment were published in a recent edition of the journal of the European Molecular Biology Organisation (EMBO), and the work was funded by Cancer Research UK and Breakthrough Breast Cancer.

Simply put, the researchers took human breast cancer cells that were grown in the lab, divided them into different samples, and reduced or ‘knocked down’ the activity of specific genes one by one. In total, the team tested a panel of 779 genes, the majority of which were for kinases – genes that play an important role in sending signals within and between cells.

Then they treated each of these samples of cells with PARP inhibitors, to see if the combination of the two proved lethal. The experiment threw up a number of exciting results, and when the activity of at least six kinases was reduced, PARP inhibitors had a dramatic effect.

Now the challenge will be to identify patients whose cancers carry these faults, to see if PARP inhibitors will work for them too. The study also proves the benefit of this kind of screen for finding potential new targets for existing drugs.

Kat