Cancer therapies that target DNA damage repair

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Published: 11 Jan 2011
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Prof Stephen Jackson - University of Cambridge, UK

Prof Stephen Jackson speaks to ecancertv about cancer treatments that target cells’ ability to repair DNA damage. Cells are constantly damaged by influences such as UV light and radiation and consequently have systems in place to repair this damage. Prof Jackson's group developed Olaparib, a drug that targets the PARP repair enzyme in BRCA mutation positive breast or ovarian cancers. Prof Jackson discusses the potential to develop additional drugs that will target different damage repair enzymes which could be used to treat other cancers and talks about the session he will be chairing on this subject at the 2010 NCRI meeting.

NCRI Cancer Conference 2010, 7 November 2010, Liverpool

Professor Stephen Jackson – University of Cambridge, UK

Cancer therapies that target DNA damage repair

Well I gave a broad overview of how cells in our body respond to DNA damage. DNA damage is going on in our bodies all the time in addition to being caused by ultraviolet light, chemicals, radiation and whatever, and it turns out that in our cells there are special mechanisms to repair the damage and put it back together again, which is good. Sometimes it goes wrong and that gives rise to cancer, so understanding these events helps us explain how cancers occur but it also provides opportunities for coming up with new therapies for cancer.

We know now that certain cancers actually have defects in certain ways of repairing DNA damage. That means they are more vulnerable to certain DNA damaging agents such as chemotherapy and radiotherapy, but what we found is that that makes them very, very dependent on another DNA repair pathway. So certain cancers lack one repair pathway, it makes them very dependent on the other. And a few years ago, based on that concept, I founded a biotech company out of my academic work which has basically developed drugs targeting the other pathway, and what we find, it’s very exciting, is that those drugs do not affect normal cells very much but are very toxic against certain hereditary breast and ovarian cancer patients, cancers which have defects in the genes called BRCA1 and BRCA2.

Can you tell us about some of the drugs that you are developing?

This work so far, which was carried out by the company  KuDOS that I founded and latterly Astra Zeneca which acquired  KuDOS, is targeting a repair enzyme called PARP and the compound we developed called Olaparib is now in late stage clinical trials; very exciting data. But we believe that’s just the tip of the iceberg, that that’s established one concept, a concept for attacking certain classes of cancer, but we know there are other classes of cancer that might be targeted by inhibiting another DNA repair pathway. And just to summarise, we’ve recently discovered in my academic group in Cambridge University, another enzyme which plays a key role in a certain DNA repair pathway and we believe that by drugging that, developing drugs against that enzyme, we will be able to target a different set of cancers than are currently being treated by PARP inhibitors.

Which cancers will you be able to treat with these new drugs?

It will be a range of cancers. The issue is that traditionally treatments have been based around if you’ve got breast cancer you’ll get one treatment, if you’ve got brain cancer you’ll get another treatment, but it’s clear that when you look inside a certain category of cancers there are different molecular readouts. So maybe 10, 20, 30% of cancers, breast cancers, will be treatable by agents that are being developed now; we believe that maybe another 10-20% of breast cancers will be targeted by a new enzyme, and we will see hopefully very similar things in other kinds of cancers: pancreatic cancer, lung cancer. It’s still too early to know what percentages and precisely which cancers, but I think there is quite a big potential there.

When can we expect these drugs to impact clinical practice?

Well of course it would be nice to develop a new drug tomorrow, but unfortunately that isn’t really the way things are. Things take a little bit longer than that, but the technologies have developed a lot over recent years so drug discovery, drug development and evaluation are much more effective than they used to be. So I am, at the moment, thinking that five to ten years, hopefully closer to five years, five, six, seven, we could be in a position where there might be new drugs entering the market that cancer patients and their doctors will be very excited to see.

Can you tell us about the session you are chairing at NCRI 2010?

I gave a talk this morning focused on this work I’ve just talked to you about but this afternoon I’m chairing another session where I’ve managed to pull in three very highly respected international scientists from Europe and from the UK who are going to talk about additional ways of targeting DNA repair pathways, to try and come up with yet further ways of treating cancer, but also use markers of DNA damage as better diagnostic factors to hopefully earlier diagnose cancers and maybe identify which cancers are going to respond best to which type of treatment.