3rd EurocanPlatform Translational Research Course
Mouse models for complex aspects in human cancer
Dr Peter Bouwman - Netherlands Cancer Institute (NKI), Amsterdam, Netherlands
The main message of my talk is actually that we need mouse models in cancer research because cancer is a very complex disease and it doesn’t only involve inactivation of tumour suppressors or activation of oncogenes but also an interplay with all the normal cells around it and also immune cells around it. This can only be properly investigated in mouse models.
What significance does this have for changing clinical practice?
The thing is that there are many possible drug targets and there are also many drugs already on the market, so drugs being developed. But many of the drugs that are in development are actually not reaching phase III clinical trials even. So we’re not doing good enough in cancer drug development so there’s clearly a need to do better and we think we really need to have better models for cancer to do this and not only rely on cell culture experiments.
Can you tell us about the models you have developed for studying breast cancer?
We have developed several breast cancer models to study many different types of breast cancer. We have focussed on BRCA1 and BRCA2 breast cancers mainly in the last couple of years and these cancers are very sensitive to specific types of inhibitors, PARP inhibitors that are just recently approved now to be used in the clinic. Now with these new drugs it will be very important to know already, as early as possible actually, how patients will respond. We know unfortunately that in many cases at some point there will be resistance to therapy so we have been focussing quite a bit on looking at resistance mechanisms in our mouse models. We’ve been treating these mice with PARP inhibitors and when resistant tumours appeared we have been looking on what would cause these tumours to be resistant.
What are the next steps for this work?
The next steps will be to actually try to make the transition to the human situation. That’s really important so we are not only working with genetically engineered mouse models we’re also working with patient derived xenograft models in which we have real human tumours. It will be very important to also manipulate these tumours and see if we can get even closer to the human situation with those.
What are the current obstacles to this work, apart from money?
Current obstacles are that mouse work is still very time consuming, that’s really a big obstacle. Fortunately also here there have been recent innovations that will probably help us to become much faster and the CRISPR Cas technology is, for instance, a very potent and powerful way to develop new mouse models and to do further analysis of genes that may be important in tumour formation and also in treatment response.
What will be the eventual benefit of this work?
Our work would help us to have better therapy and better stratified therapy for patients with specific mutations. It will be important to know already at an early stage if certain tumours are likely to become resistant to therapy, if certain tumours will do very well with a certain type of therapy. So those things we hope to learn already in advance, actually.
Do you have a take home message?
With our preclinical work we can already in the very early stage know what type of resistance mechanisms are possible for certain types of treatment like PARP inhibitors. Knowing that, we can also already try several alternative strategies to eradicate these tumours. So it will be very important to invest more in this type of research to eventually help patients.