In this blog we step back in time to the work we supported in the discovery of the gene BRCA2, and the research that followed, which contributed to the discovery of a whole new way to treat breast cancer.

Wednesday 15 April 2015      Research blog
Drugging PARP: severing cancer’s Achilles’ heel

Cracking breast cancer genetics

Our journey begins in the 90s, around the time when Wet Wet Wet were serenading us with Love is all Around and Whigfield was getting us all to do a certain dance on a certain night of the week. There was a lot of excitement in the breast cancer research community, following major discoveries identifying the first genes that, when faulty, could be linked to breast cancer.

Then the year 1994 saw the discovery of such a faulty gene in some breast cancer patients; they called it BReast CAncer 1, or BRCA1 for short. In 1995, with support from Breakthrough Breast Cancer, scientists also discovered a second breast cancer susceptibility gene and named it BRCA2

In the years that followed, researchers figured that both BRCA genes were involved in the incredibly important job of repairing damaged DNA in cells. DNA must be kept intact and error free so that the genetic code it contains can be used properly. When the genetic code is corrupted, it can lead to cancer. This, unfortunately, is what can happen to cells containing a faulty BRCA gene.

Not just a cause

Now let’s fast forward to 2005. The year Tony Christie was once more asking for the way to Amarillo and Prince Harry made a slight wardrobe faux pas at a fancy dress party. At around the same time, our scientists at the Institute of Cancer Research were about to publish some ground-breaking work with their collaborators at the University of Cambridge.

Building on a wealth of research looking into the mechanisms of DNA repair and how this goes wrong in cancer cells, the dynamic duo of Breakthrough’s Professor Alan Ashworth and Cancer Research UK’s Professor Steve Jackson were about to show the world their discovery – that the inherent weakness of cancer cells, caused by faulty DNA repair, could be used to bring the cell to its metaphorical knees.

Targeting the genetic weakness

BRCA1 and BRCA2 are very important molecules, helping to repair our DNA and protect us from cancer. But there are many other molecules involved in DNA repair – one of which is called PARP (short for Poly ADP-Ribose Polymerase). This molecule plays a crucial role in the repair of breakages in DNA, but works in a slightly different way to BRCA1 and BRCA2.

In a smash hit with the journal Nature, and in an incredibly clever piece of science, Professors Ashworth and Jackson tested out the theory that cancer cells that already had faulty BRCA molecules wouldn’t be able to survive if they also lacked PARP.  To do this they performed a series of experiments. 

Let’s take a look at what they found.

Firstly they looked at what happened to cells grown in the lab that lacked either BRCA1 or BRCA2 to see what would happen when they also reduced the amount of PARP using a new drug called a PARP inhibitor.  They found that reducing PARP levels in cells with faulty BRCA genes caused them to stop growing or die.  Importantly, cells with a working BRCA1 and BRCA2 weren’t sensitive to the drug, or at least not to anything like the degree to which the cells lacking BRCA were.

This all suggested that these sorts of drugs would do a very good job of selectively targeting breast cancer cells carrying BRCA faults. Or at least a much more selective job than chemotherapies which target all cells in the body that are dividing lots and lots, which includes many healthy ones like the skin and hair follicles.

Unable to repair

So what was causing this sensitivity to these PARP inhibitors? Professors Ashworth and Jackson took a closer look at what was happening to the cells lacking BRCA when treated with the PARP inhibitors and found that they were getting stuck in the cell cycle – the process by which cells divide.  When these cells were stuck in the cell cycle it led to the cells effectively committing suicide.

A detailed inspection of why this might be happening showed that the PARP inhibitors were causing major damage to the cell’s DNA. Ordinarily, cells without a working BRCA to repair the damage rely on PARP to clear up the mess. But with the drug also blocking PARP, the only option was for the cell to try to use cruder, error-prone methods such as trying to glue the ends of bits of DNA together. The level of damage left in the wake of these PARP inhibitors was irreparable in cells with faulty BRCA, leading to their eventual death (watch the awesome video at the end for more on this).

Proof in people

The next step was to see if something similar was happening in a cancer setting, rather than just in cells that happened to lack BRCA. Could the treatment with PARP inhibitors kill off tumours with a faulty BRCA gene? Using mice, they found that the PARP inhibitors severely inhibited the formation of tumours derived from cells with faulty BRCA2. This was the first indication that such an approach could have therapeutic potential to treat cancer in patients.  

What made this news even better was the suggestion from the authors that treatment with PARP inhibitors wouldn’t necessarily be limited to patients carrying BRCA faults. It could also work in patients whose cancer had faults in other DNA damage repair mechanisms, including –but not limited to – the one that involves BRCA. So these drugs could be suitable for many patients with many types of cancer.

Needless to say this discovery generated a huge amount of excitement and, together with research taking place in Newcastle, led the way for these sorts of treatments being successfully tested in patients.

PARP inhibitors were once billed as one of the next generation of cancer treatments, but that generation is now all grown up.  Developed in the laboratory, they have been tested on cells in petri dishes, proven to work in animals and shown great promise in humans. 

The last decade of research has seen these drugs get a stone’s throw from being made available for widespread use where they can provide many more cancer patients with effective, targeted treatment.  We were therefore delighted to hear that the PARP inhibitor Olaparib has just been given the green light by the European Medicines Authority to be given to patients within the European Union. We are extremely proud to have played a significant part in bringing new hope to those affected by cancer.

Dr Sarah Hazell – Senior Manager Research Insight and Innovation