EACR 21, 26—29 June 2010, Oslo

Professor Thomas Helleday (Gray Institute for Radiation Oncology & Biology, Oxford, UK)

The role of homologous recombination in cancer

I’m based in Oxford at the Gray Institute, which is a fairly novel institute that is focussed primarily on radiation, oncology and biology. I’m also based in Stockholm at the Stockholm University where I do more basic science and I do a lot of science into DNA repair. The overall aim is to develop new cancer therapies and bring them into the clinic.

I won the Carcinogenesis Young Investigator Award, I’m very pleased with that and one of the main reasons for it is probably because of our discovery of the PARP inhibitors and how they could selectively kill recombination defective cells. So this is a concept of having an inhibitor that is not very toxic that then can selectively kill recombination defective tumours such as inherited breast and ovarian cancers. This has now been used in the clinic and it has received a lot of attention and we see a good response in a few patients, which is very intriguing, and we want to continue on this concept. So we believe that this concept will be very useful for the future development of anti-cancer strategies.

How does ‘homologous recombination’ impact cancer?

Recombination impacts on cancer on very many levels. First of all it’s inactivated very early on in cancers to develop genetic instability that then causes gene rearrangements and mutations that make the cells differ from normal cells so that they can develop into cancer cells.

So it’s very important in the development of cancer. It’s very important when it comes to therapy because recombination is involved in repairing replication lesions and most chemotherapy that we have today, also radiotherapy, depends on recombination for survival. So this means that cancer cells are more sensitive than normal cells so we can kill off the cancer cells with chemotherapy and radiotherapy in order to get rid of the cancer. So it has a very important implication for the treatment of cancer which is helping us to actually use chemotherapy.

Not only that but it’s unfortunately involved in resistance as well, so recombination is activated in some of the cells to become resistant to therapy and now we have very big difficulties to target these tumours and this is a very important reason for chemotherapy to fail. Once chemotherapy has failed then you get resistance in patients, unfortunately that’s the time when the patient usually will not much longer be with us.

How can this be exploited for cancer therapy?

We can exploit them on many different levels. First of all we can, instead of using chemotherapy to target the tumours in the first place that are recombination defective, we can use more tailored strategies such as the PARP inhibitors which do not give the side effects as the other, old chemotherapies do. Most importantly, and what my lab is focussing on at the moment, is to develop inhibitors for the resistance mechanism because the resistance to chemotherapy is the reason why patients die from cancer. So we want to develop inhibitors for recombination in order to resensitise the cancers so that we now can target them.