PARP inhibitors

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Published: 20 Jul 2010
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Professor Hilary Calvert - University College London, UK
Prof Calvert speaks about his current work at UCL developing phase I and translational research in addition to working with the UCL bioscience department to develop novel cancer treatments. Prof Calvert explains the background to his work developing PARP inhibitors and outlines how these drugs are likely to be effective in some tumours that do not have the non BRCA mutation but do show BRCA-like phenotypes. Possible future developments include the use of PARP inhibitors as a chemo-preventative drug in patients who are known to be BRCA carriers.

ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Professor Hilary Calvert (University College London, UK)

PARP inhibitors

Professor Hilary Calvert, what are you doing at the University College London?

My brief there is twofold, really.  One is to build up more Phase I and translational medicine programmes in the UCL Cancer Institute, and in the clinical research facility there, which is new and very well equipped. The second, which to me is the most exciting thing, is to link up with the UCL bioscience, which is some of the best in the world, and see if I can identify and start cancer drug discovery projects  based  on novel bioscience discoveries.

Have you got funding?

We’ve got to work on the funding for that. We’ve got funding for the Phase I programmes.

You started work on the PARP1 inhibitor about 20 years ago. Tell us what happened?

Well, when you move into a new department, then normally the person who left takes all the good people with them, and in Newcastle that wasn’t entirely the case, because one person stayed and that was Barbara Durkacz who, as a post-doc, had been the first one to clone what was then known as the PARP gene. Of course, we didn’t know there was more than one. And she had data on chemosensitising. So, when we wanted to set up drug discovery, it seemed like an obvious target. We had world-class expertise in the lab which you always need to make drug discovery work. And nobody else was doing it, and it worked with drugs that we knew about.

Now, to be honest, the chemistry went well and we got good inhibitors relatively soon. But whenever I used to present work on the PARP inhibitors, everybody sort of had a stony silence and there wouldn’t be any questions. And then somebody would get up and say, it’s pretty stupid to try and inhibit a housekeeping enzyme.  Slowly we convinced people and got through, and prepared for a Phase I on our lead compound. We were ready for Phase 1 in 1998, but, in fact, due to a takeover of the Pharma company with whom we were collaborating  we didn’t get to do it until 2002.

But, of course, the thing that really put spice into the PARP field and got it into the plenary sessions at ASCO and ESMO, was the discovery that PARP inhibitors are selectively toxic to BRCA-mutated cells, and that didn’t come until 2005. It was discovered simultaneously by Nicola Curtin in our group, who was collaborating with Thomas Helleday in Sheffield who worked on BRCA cell lines, and by Alan Ashworth in the Institute of Cancer Research in London who was collaborating with KuDOS, who were also making PARP inhibitors because they’d got the idea from our programme.

So two separate groups found the application at once, and that gave plausibility, because we both used different models of BRCA deficiency and we both used different chemical classes of PARP inhibitors, so it made it very clear it was a generalised phenomenon that was due to PARP inhibition, not some off-target effect on the part of the PARP inhibitor.

The results are gratifying from oral PARP inhibitors and also IV PARP inhibitors?

Pretty much all the studies that have been done have shown activity in BRCA-mutated tumours. I think what’s becoming even clearer now, which we suspected a while ago  is that the activity won’t be restricted to patients whose tumours are due to BRCA mutations because a lot of tumours have deficiencies and homologous re- combination that gives them a BRCA-like phenotype, and the potential to respond to PARP inhibitors. It could be that in as many as a third of solid tumours there may be a role for a PARP inhibitor.

That’s fascinating. And that’s really tantalising. I mean, there’s a small paper here on ovary suggesting that in BRCA wild type patients with ovarian cancer, there are responses?

Absolutely

And that would suit your theory pretty well.

Yes

And what would you do with your PARP1 inhibitor now that you’ve got this result? Your lab people realised that you were talking sense all along. What’s the next step for you?

Well, I think the next step is to develop combination studies, and this is being done on a wide scale because there are nine PARP inhibitors in clinical development now. So, not only do Pharma believe the original story, they want one of the inhibitors too. There probably will be a few more by next year.

You’re already running into some interesting issues with combinations versus sequencing – giving PARP inhibitors after drugs like platinum. How do you think that’s going to pan out, or is it just wait and see?

I think, at this point, we have to confess clinical medicine is sometimes an empirical science and we should do the trials to find out. I think there’s another interesting possibility with PARP inhibitors which has been controversial, but I still think it’s worth mentioning. That is that there’s a possibility you could use them for chemo prevention in patients who are known to be BRCA carriers, because they have a very high lifetime chance of getting a tumour.

What we know about the synthetic lethal mechanism in BRCA mutations, is that the less downstream mutations that have occurred, the better the PARP inhibitor will work, so that if you gave somebody a course of a PARP inhibitor in a prophylactic way, if there were just a few cells that had acquired the first deletion of the second allele of the BRCA, you’d almost certainly kill them. And if you repeated that, maybe, every year or every two or three years, you might prevent them ever developing a BRCA-related cancer.

Do you think the toxicity profile is going to work out okay for a chemo preventive study?

The subjective toxicities and the short term toxicities of the PARP inhibitors are minimal. It varies a little bit according to which analogue you’re using. So, the concern would be the potential genotoxicity of giving a PARP inhibitor, but the argument against that, as you’ve pointed out, is that we already find it acceptable to give drugs for cancer prevention which are mildly genotoxic, and that the cancer risk in the BRCA carriers is getting on for 100%. So, some risk of prevention would be acceptable.