The DNA damage response

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Published: 22 Dec 2015
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Dr Helge Gad - Karolinska Institutet, Stockholm, Sweden

Dr Gad describes his research investigating inhibitors for DNA repair proteins in cancer cells, at the 3rd EurocanPlatform Translational Research Course. He explains what significance this could have in clinical practise, particularly in terms of developing new drugs for instance with PARP inhibitors at the Helleday Laboratory.

He also outlines the next steps and what obstacles they face in this line of research.

 

3rd EurocanPlatform Translational Research Course

The DNA damage response

Dr Helge Gad - Karolinska Institutet, Stockholm, Sweden


DNA repair, so DNA damage response, is very important for the cells, especially for the cancer cell. The cancer cells have deregulated DNA repair in different ways. So the main focus of the talk and also in the lab is to find new cures for cancer, actually develop inhibitors against DNA repair proteins that are essential for cancer cells but have as small effect as possible in normal tissue.

What significance does this have for clinical practice?

We are actually developing new drugs ourselves in an academic setting. So I’m part of a big research group that consists of both chemists but also cell biologists, that’s myself, but also in vivo pharmacologists and physicians. So the idea is to have a whole chain from the chemical biology side until clinical trials. So I believe that although it’s difficult and we haven’t succeeded yet to bring a drug to the patient, that’s our goal.

Can you tell us about the drugs you’ve been working on?

So Thomas Helleday, who I work with, he has a long history in DNA repair so he works with the PARP inhibitors. They target BRCA deficient tumours and they have recently been FDA approved, so drug which is the drug that was licensed out by Thomas. So PARP inhibitors are already in the market and actually treating patients so we actually have contact with patients getting PARP inhibitors and it’s very nice. So the new thing that I will talk about is new targets and we have a new target called MTH1 which is involved in oxidative stress or oxygen damage repair. We think that that target also potentially could be a treatment for many types of cancers.

What are the next steps?

It’s to approach the clinical side now so we have a clinical candidate which is a more advanced drug which we will try to bring into clinical trials. We are actually doing this in open innovation type of work so it’s collaborations. So far it will be collaboration with Cancer Research UK, which has approved this study in their work. So that’s very exciting we think so now we are moving into studies to get approval to be able to use these compounds and inhibitors in the clinic.

Besides money, what obstacles have you faced?

I come from an academic background and working with chemical compounds, small molecules, is very difficult. You realise how many obstacles there are. It’s that you don’t understand the whole system, basically. The cell is so complex and especially the cancer cell and when you work with small molecules you realise that there are no specific inhibitors out there. So they’re doing many things and that’s to understand what you looked at is really what’s happening and that’s one, so the basic science part. But it’s also, going to the clinic, it’s also for finding a good compound that has good availability in the animal or in the patient and you find the target inside the tumours. So far we just used mouse models and we have used patient derived xenografts, which is tumour cells isolated from patients that are grown in the mice, then treated. So that we have seen good effects but I know that it’s a big step towards the clinic to have real tumours in patients. So that’s a big obstacle actually.