EACR 2016

ß1 integrins and DNA repair for radiosensitization of head and neck cancer

Dr Nils Cordes - Center for Radiation Research in Oncology, Dresden, Germany

Today I talked about the connection of integrin cell adhesion receptors and DNA repair. This is very novel and we were the first to touch this subject because we know that when you inhibit ß1 integrin, which is one of the central integrins, then you radiochemosensitise cancer cells. So in particular when you use DNA damaging agents then you obviously think as a next logical step that you address whether this also impacts on DNA repair. So we investigated whether there’s a mechanistic connection between the membrane signalling of ß1 integrins and events in the cell nucleus with regard to the repair of DNA double strand breaks.

What led you to this research?

We did that in head and neck cancers because head and neck cancers desperately need optimised therapy. In the last thirty years hardly anything had changed and so we are looking for optimisation of therapy by biological modulating receptors or protein kinases. To be more physiological, we have established over the last ten years 3D matrix-based cell cultures in which cells are embedded in a physiological matrix similar to the body and this really impacts on all levels of cell physiology like genetics, epigenetics, signal transduction. So that is one of our models which we use in over 90% of our projects. The other thing is that we use tumour xenografts in nude mice. With these two we measure different endpoints like survival and DNA repair and then we use other techniques to address the mechanisms like Western blot, immunoprecipitation, mass spectrometry, phospho-proteome arrays, just to have a broader view on the signal transduction which is either mediated or modulated when we have a therapeutic intervention.

Can you apply these techniques to other cancer types?

Yes, we have shown that in the last ten years or so in many different other tumour entities like glioblastoma, lung cancers, pancreatic cancers, so particular cancers which are cancers of unmet need, so addressing really glioma, pancreatic cancer and head and neck. Also we have done this in haematological tumours because all our things, obviously when we talk about cell adhesion and how this impacts on therapy resistance is also true for leukaemia, for lymphoma and not only for solid tumours. So this is of particular interest and importance.

Do all cancer types show the same levels of resistance?

The impact of cell adhesion on their resistance is different, a little bit depending on the genetic and epigenetic alterations seen in these cancers. Nonetheless it depends on either integrins or other proteins which are associated with these integrins, when we target them how sensitive they are or how susceptible they are on top of radiochemotherapy. What is one of our really big main interests is that we want to identify bypass signalling pathways which are induced by a particular molecular intervention. So, for example, when we use either integrin targeting or EGF receptor targeting, which is already in the clinic, then we do not hardly know anything about which pro-survival signalling pathways pop up when we have this intervention. This is important because then we can easily identify the signalling hubs which are important and we can inhibit them. Then we see an additional impact on radio- or chemosensitisation, so with regard to multi-targeting, with regard to precision cancer medicine.

Would you give this therapy in combination with radiation?

Yes, this is very important because all the things we are doing we are doing on top of radiotherapy or even radiochemotherapy because these conventional therapies will still be in the clinic in the next decade or two decades. Nonetheless we are all interested in more molecular therapies and more individualised therapies, however these conventional therapies we have to always consider them because they will be in the clinic for a long time. All the molecular drugs will only be on top of radiochemotherapy. So this is important because also upon radiation and chemo resistance mechanisms are acquired and induced and so combining this would give us another level or another dimension of opportunities.

Considering we’ve had radiotherapy for so long, why are we hearing more about radio-resistance now?

The question is is that acquired or intrinsic resistance? Most of them are intrinsic due to genetic and epigenetic alterations and the microenvironment, for example hypoxia or growth factors and all this, what is in the microenvironment which really impacts on the intrinsic sensitivity to therapy, including radiotherapy. The question is what exactly is the cause of resistance to radiotherapy is unknown. There are quite a number of groups which repeatedly irradiate cells and see different mutation patterns and this is in the beginning of research so we will see in the next 5-10 years.