The DNA damage response and cancer therapy

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Published: 6 Jan 2015
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Dr Christopher Lord, The Institute of Cancer Research, London, UK

Dr Lord talks to ecancer at the 2nd EurocanPlatformTranslational Research Course, discussing his work on the concept of ‘synthetic lethality’, PARP inhibitors and the lessons his lab have learned whilst developing new approaches to treating cancer.

He also covers the obstacles facing this work and how it could impact clinical practise.

Learn more about the EurocanPlatform project here

The work I presented mainly focussed around using this genetic concept known as synthetic lethality. Synthetic lethality describes a situation where you combine a mutation in a gene with a drug to kill tumour cells. So the way in which we’ve been using this concept of synthetic lethality is to try and devise new approaches to treating cancer. One of the things that we came up with was using small molecule PARP inhibitors in patients that have BRCA 1 or BRCA 2 mutations. So most of my presentation talked about that but it talked about the lessons that we, in our lab, have learned in developing these ideas around synthetic lethality and PARP inhibitors but also the lessons that we’ve learned that we can now apply to try and identify new targets for using in patients with cancer. The main lesson that we learned in the past ten years in this work was that it’s very important to make sure that the biological hypothesis that you generate in your preclinical work, that is actually pursued when drugs go into clinical testing. That sounds kind of obvious but actually very often drugs go into clinical trials and they’re not necessarily used in the way that the people who are working on the original preclinical work would suggest they would use them. So following that preclinical device hypothesis is very important. I think many of the people who have been speaking at the symposium have been reinforcing similar messages.

What is the significance for clinical practice?

The obvious significance of what we’ve done actually concerns using PARP inhibitors and getting those into clinical practice. The somewhat broader significance is using this concept of synthetic lethality to try and identify different ways of treating the disease. Up until the time when people started applying this concept, one of the other concepts that people focussed on was an idea known as oncogene addiction and actually now it’s becoming more common to use this concept of synthetic lethality to think about different ways of treating the disease. Again, you will see many of the people who spoke here are now using a very similar concept.

What are the main obstacles and eventual benefits of this work?

The most important point I was trying to make in my presentation was not necessarily an obstacle but again it’s this idea of following the original biological hypothesis into clinical testing. Actually this is quite difficult to do sometimes. What we are originally proposing is actually to take a relatively well defined, relatively small percentage of the cancer population and trial PARP inhibitors in those patients. That actually raises quite a challenge, both pragmatically and economically for the people who are paying and running drug trials but is actually probably one of the ways in which you maximise the chance of drugs succeeding in clinical trials. So it’s not necessarily an obstacle but we just want to highlight that following through that biological hypothesis into a clinical trial setting is not always as straightforward as it might be.

What are the next steps?

There are very immediate steps so there are now a range of PARP inhibitors being tested in the clinic and some of those are going in to phase III trials. So the hope is that in the next couple of years those trials will report and one or many of the PARP inhibitors will be licensed. Then again, more broadly, the future is more and more groups are increasingly applying this idea of synthetic lethality to come up with alternative ways of treating cancer but also to think about not necessarily identifying new targets but to use a drug that we already have in slightly more refined ways. So it’s using the idea might be the longer term significance of what we’re doing.