Deciphering RAS/MAPK signalling in cancer

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Published: 13 Jul 2016
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Dr Mariano Barbacid - CNIO, Madrid, Spain

Dr Barbacid speaks with ecancertv at EACR 2016 about results from novel mouse models to target KRAS mutations in cancer.

He describes how integrated recombinase systems, which enable the controlled expression of genes in vivo, have generated models with more readily actionable tumours for genomic and therapeutic analysis.

He also addresses recent developments in combination therapies, with regard to the risk posed by cumulative toxicity, and future of personalised therapy.

 

EACR 2016

Deciphering RAS/MAPK signalling in cancer

Dr Mariano Barbacid - CNIO, Madrid, Spain


My laboratory has been interested for many years in trying to find selective therapies against KRAS mutant cancers, specifically lung adenocarcinoma and pancreatic ductal adenocarcinoma, pancreatic tumours. So what I presented are our efforts using genetically engineered mouse models to try to identify targets that are therapeutically effective because in industry now are developing a lot of inhibitors against many targets but we still have to understand, or have a better understanding, of how the KRAS mutant oncogenes signal to be able to be a little bit more successful in the clinic.

Could you tell us about your use of next generation mouse models?

Many of the studies that have been published thus far with genetically engineered mouse models, what they target is the initiation process. In other words, they eliminate the target or inactivate the target at the same time that the oncogene is expressed. So this is not what you find in the clinic, in the clinic people really, unfortunately, come with tumours and not only tumours, very advanced tumours. So now what we have developed is a next generation of GEM models in which we induce the tumour with one recombinase system, the FRT-FLP based system, and then once the tumour has been formed, and obviously you can have mice with relatively small tumours or mice with very large tumours, then we eliminate the target using another recombinase system, the most commonly used system, the Cre-Lox system, which is more efficient and then we determine what is the therapeutic benefit derived from eliminating that target not during the initiation process but in an already formed and many times very advanced and aggressive tumour. So we think that that data, those results, are much more applicable to the clinical setting than just inhibiting initiation of tumour development.

Where do you see your research heading in the near future?

I’ve been in research long enough to not like to predict what is going to happen. Look at immunotherapy – who would have predicted the big success in melanoma? On the other side, the negative side, just three or four years ago then we really learned about tumour heterogeneity. So I don’t like to predict. The only thing I can tell you for sure is we will be better off in five years than we are now but how much that is not for me to say.

What is your opinion on combination therapy?

Combination therapies are a must. Anybody that sees the complexity of the cancer genomes will be a fool thinking that just a single drug can cure it. The problem with combination therapies is not so much combination therapy but the cumulative toxicities. Right now probably there are enough drugs to block five or six pathways that probably we are in a position to block tumour progression and even induce very effective tumour regression. But these drug combinations cannot be used because they are too toxic; there is what we call cumulative toxicity – a drug is a little bit toxic, two drugs more toxic, three drugs probably too toxic. So obviously one of the areas is to develop drugs that are less toxic and this is the realm of the medicinal chemist but also we biologists need to identify targets that are only relevant for the tumour signalling, the oncogenic signalling, and not relevant at all for the normal counterpart. So then we could have drugs that have minimal, if any, toxicity and then once we have that then you can use combinations of five or six drugs. But until we are able to, either by making better drugs or by selecting better targets, reduce the toxicity of a single drug, each by themselves, until then we cannot combine them because if we combine them we just reach intolerable toxicities and patients just cannot take it.

Regarding personalised medicine, will the various selected targets be different in each cancer patient?

Success is going to be tumour by tumour. Sometimes there will be major advances in a particular tumour type as we have seen with metastatic melanoma and immunotherapy. Clearly we are going, as I was saying before, we are going to make progress but how fast and in which tumour type is very difficult to predict.

What technologies would you like to see developed further in the near future?

What is very important is that clinical work talks a lot to experimental work and vice versa. This idea of going from the lab to the clinic and from the clinic to the lab is very important that the information is in both directions because only studying clinical samples we will be able to know what are the relevant mutations in real tumours. But then you cannot experiment with humans, you need to take these tumours, put them back in the lab either with PDX models or organoids or cell culture or maybe making new third generation genetically engineered models, so experimental systems that really mimic what is going on in the clinic. Here you do your research and once you get good results then you send it back to the clinic and see whether these results really have a benefit for the patients. But it has to be a very fluid communication between the real world, the clinical samples, the patients and the experimental world which is primarily mouse although obviously I don’t exclude other model systems. But these days it’s primarily mouse or, as I said, organoid systems that are also very useful.

What are your thoughts on EACR?

Thus far it’s the best EACR meeting I have attended. I have interest in all of them, some of them it’s just curiosity, the immunotherapy because right now we are not working on that; certainly drug resistance is also very important because it’s a fact that we all have to deal with. In general I find all the sessions I have attended thus far very interesting.