Widening the net for PARP inhibitors

Blocking PARP in combination with other molecules could be a powerful way to treat cancer.

We’ve previously written at length about PARP inhibitors – drugs designed to target the genetic ‘Achilles’ heel’ in cancers caused by faults in the BRCA1 or BRCA2 genes. Our scientists and doctors have been working on these drugs for more than 10 years, and investigating the fundamental processes that underpinned their development for decades before that.

PARP inhibitors are already showing promise in clinical trials in women with ovarian or breast cancer caused by one of these faulty genes. But researchers think that they could have much wider applications beyond the relatively small proportion of cancers that are due to BRCA faults.

In May, we described how researchers in the Netherlands and the UK have discovered that heating up cancer cells could make them more susceptible to the effects of PARP inhibitors, regardless of their genetic makeup.

Last week, Cancer Research UK scientists at the Northern Institute for Cancer Research in Newcastle found another way to increase the possibilities for PARP inhibitors, paving the way for the development of drugs that could be used to treat a wide range of different cancers.

Targeting ATR

PARP inhibitors work by preventing cancer cells from repairing certain types of damage to their DNA. Most healthy cells have other ways of repairing DNA damage so they aren’t affected by the drugs, but cancer cells with faulty BRCA1 or BRCA2 can’t carry out these repairs. The combined effect of knocking out both DNA repair mechanisms is so severe that the cancer cells die.

To use an analogy, cells with a faulty BRCA gene are like a table that’s had one of its legs knocked out from under it. It can still just about function, although it’s a bit wobbly. Knocking out the other leg (using PARP inhibitors) makes the table completely unstable and it falls over.

Led by Professor Nicola Curtin, the Newcastle team have been pioneers in the development and testing of PARP inhibitors. But they’re keen to expand the potential use of the drugs beyond their current experimental use in breast, ovarian and prostate cancers caused by BRCA faults.

To do this, the scientists searched for other DNA repair mechanisms to block that might prove fatal for cancer cells in combination with PARP inhibitors. This approach is known as ‘synthetic lethality‘, and it’s providing several exciting leads for possible future cancer treatments.

One such potentially ‘lethal’ partner for PARP inhibitors is ATR – a DNA repair protein that has been known to be involved in cancer for more than a decade. Unfortunately, ATR has proved to be a reluctant target, and attempts to develop drugs to block it have had little success.

But then the Newcastle team made a serendipitous breakthrough.

A stroke of scientific luck

More than a decade ago, the Cancer Research UK team and their colleagues at Newcastle University developed a chemical called NU2058, originally designed to target a molecule called CDK2, one of the key components of the molecular ‘engine’ that drives cell division.

However, researchers discovered that the compound wasn’t actually working in the way they thought, and didn’t seem to be targeting CDK2 alone.  The results suggested NU2058 was also acting on something else – but what?

The scientists noticed that NU2058 and a related chemical, NU6027, made cancer cells much more sensitive to the effects of the chemotherapy drug cisplatin. This looked strangely similar to the effects of cisplatin on cells lacking ATR. Could it be that the chemicals were actually the elusive ATR-blocking drugs that they had been searching for?

Testing the theory

To find out, the researchers carried out a range of tests with NU6027 using cells grown in the lab, including breast and ovarian cancer cells as well as fibroblasts (a type of cell found in connective tissue).

They discovered that NU6027 was an effective inhibitor of ATR in cancer cells, blocking its activity at relatively low doses. And using the chemical along with DNA-damaging chemotherapy drugs such as cisplatin was a potent combination, making cancer cells much more sensitive to the effects of the treatment. But the chemical had no effect in combination with paclitaxel – a drug that works in a different way, by stopping cancer cells from building the ‘scaffolding’ they need to divide.

The results suggested that NU6027 was stopping ATR from repairing DNA damage in cancer cells – to use our wobbly table analogy, it was knocking out one of the ‘legs’. To see if they could knock out the other one, the researchers tested the combined effects of NU6027 and an experimental PARP inhibitor.

The results were impressive – the combination of blocking ATR and PARP together dramatically reduced the survival of breast cancer cells compared to treatment with the PARP inhibitor alone.

A growing trend

The new paper from the Newcastle team is just one among a growing number of publications showing that the use of PARP inhibitors could be expanded beyond BRCA-deficient tumours – or, using our analogy again, there are several ways to knock out the ‘table legs’.

These results come hot on the heels of another paper from the Newcastle team and their colleagues at Harvard, published in the journal Nature Medicine at the end of June. As we describe in our press release, the researchers used an experimental technique to switch off a molecule called CDK1 – another part of the cell division ‘engine’ – in combination with PARP inhibitors. Given together, the two effectively killed cancer cells growing in the lab and shrunk lung tumours in mice.

And there are other examples of how our scientists are finding smarter ways to use PARP inhibitors.

In early, but potentially significant work, our researchers developed a test that could be used to widen the use of PARP inhibitors to women with ovarian cancer whose tumour cells have a faulty DNA repair process known as homologous recombination, not just those with BRCA faults. It could also help doctors pinpoint women who might not benefit from PARP inhibitors.

Using a different approach, a team based at our Gray Institute for Radiation Oncology and Biology in Oxford looked at how oxygen levels in and around tumours can affect response to PARP inhibition. Parts of tumours can have unusually low levels of oxygen – a condition known as hypoxia – because they don’t have a good blood supply.

Working closely with colleagues in Canada, our researchers discovered that – again because of defects in DNA repair –  cancer cells growing in low oxygen are more likely to respond to PARP inhibitors. They predict that future clinical trials could test the levels of oxygen in tumours to identify patients who would most likely benefit from these drugs.

What does this mean for cancer treatment?

There are two exciting conclusions that can be drawn from the Newcastle team’s research, published in the British Journal of Cancer last week.

Firstly, the findings show that blocking ATR increases the sensitivity of cancer cells to DNA damaging drugs such as cisplatin. It’s also likely to boost the effectiveness of radiotherapy, a treatment that also damages DNA. So drugs that block ATR could help to enhance the effectiveness of cancer treatment.

Secondly, the results tell us that using a combination of ATR-blocking drugs and PARP inhibitors could be a powerful way to treat many different types of cancer. Although the researchers only tested breast and ovarian cancer cells, as well as fibroblasts, ATR is implicated in a range of different cancer types, including bowel, stomach and womb cancer.

Before we get too excited, it’s important to remember that NU6027 is not yet a fully fledged cancer drug. It’s an experimental chemical that has only been tested on cells growing in the lab, and more tests are needed to see if it is suitable for taking forward as a potential cancer treatment.

Even if NU6027 never makes it to the clinic, it’s a powerful tool to help researchers studying how blocking different parts of the DNA damage repair machinery in cancer cells could be used to treat the disease. And it also throws down the gauntlet to scientists around the world, proving that developing ATR-blocking drugs is not only possible but they could also be an important future weapon in our fight against cancer.

Kat

Reference:
Peasland A et al (2011). Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. British journal of cancer PMID: 21730979