Genetics and epigenetics of lymphocyte development and transformation

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Published: 27 Jul 2015
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Dr Stefano Casola - IFOM University of Milan, Milan, Italy

Dr Casola talks to ecancertv IFOM EMBL about his research to dissect the genetic basis for responsiveness/resistance of lymphomas to current therapies.

This is a programme that actually starts and stems from basic research that is going on at the institute and actually is the follow-up of a number of investigations that our group and other groups here at IFOM have started to make with the aim to study or to identify the correlation between specific genetic mutations and the response of patients to therapies as a result of the presence of these mutations.

So the aim of this project is to actually take advantage of the basic findings that some of our groups have made studying animal models and try to translate these findings into clinical settings.

More specifically, what we basically aim to do is to select a number of genes for which we have clear evidence that they play a role in cancer development or in the response to specific therapies and try to develop genetic tests in order to use this in clinical settings to improve the treatment of patients.

Now, this programme actually is supported fully by IFOM and by the Italian Foundation for Cancer Research, or FIRC. So it’s a programme that is divided in two main parts: the initial phase will be a discovery phase where we will continue our initial discovery of genes associated with specific cancers and with the response of specific cancers to therapies that are presently being given to the patients.

Then we will try to export these findings into a clinical setting, trying to develop genetic tests that ideally should help us stratify better the patients in order to provide them with the best therapy.

Now, this programme depends entirely on the new adventures and the new venues of genome diagnostics that are being developed in different areas of the world.

What we basically do is we apply next generation sequencing technology in order to screen large regions of the genome with the final goal to identify mutations that are, according to our preliminary results, critical in providing a) a potential response to a therapy and b) could also help us define a mechanism of resistance of tumours to the current therapies.

So this is a programme that heavily relies on advanced genomic technologies and for this we have a specific team at IFOM, a technology team run by Simone Minardi who is actually responsible for sequencing biopsies but is also sequencing now what we call liquid biopsies.

So the future of genomics in cancer will be mainly trying to pick or identify mutations from the blood of patients without actually having the necessity to isolate biopsies from the tumours, this will allow us to have a very comprehensive understanding of the spectrum of mutations that tumour cells might have already when they are circulating in the blood.

So this is also an important advantage because it might allow us to identify mutations that are associated eventually with metastasis of the disease.

So a liquid biopsy will be probably the future of any genetic test that relates to understanding how tumours develop and spread in other tissues.

So the technology part is very relevant, for that we also need a core of bioinformaticians that will help us deconvolute all the genomic data that will come out from this test.

So the pool of people that will be involved in this research programme relies on basic scientists, on technologists and on bioinformaticians so it’s also a nice merge of different disciplines and different know-hows that come together in a single set-up.

The programme will start with the aim to screen a first set of candidate genes, they are in the order of 50-60 genes that we selected on the basis of the fact that they are commonly mutated in the most aggressive cancers, ranging from lung cancer to breast cancer to lymphomas, which are actually tumours we are studying in the lab.

These mutations, these genes, were also selected on the basis of the fact that for many of these mutations we have drugs that are able to target them, so target the proteins that are encoded by the mutated genes.

Therefore this information will provide us on the one hand clear and critical news on the genetic set-up of the tumour but at the same time will also hopefully help the clinician to target better the therapies and to try to identify the best drugs that will be given to the patients.

Now, the entire project, of course, depends on a very close collaboration with the clinics.

We wouldn’t exist if there wouldn’t be collaborations on-going with clinicians in the main oncology hospitals here in the Milan area, ranging from the European Institute of Oncology to the San Raffaele Hospital and the Istituto Nazionale dei Tumori.

So with many of them we have ongoing collaborations and these are very critical because we rely on one hand on the clinical records, on the other we need a very thorough description from the histology point of view of the tumours because this will really help stratify better the patients in order then to identify the right set of mutations that we should screen for them.

So this is a pool of people that have to work together in order to get this programme to work.

I want to stress again the fact that this programme is fully supported by the FIRC Foundation.

Although it’s a research programme it’s a programme that has as a final mission the possibility to give back to the society the basic findings that we make in the lab.

So the final goal of this programme is to develop a number of new genetic tests that will allow clinicians to treat their patients in a better way.

I must say for this we have also the luck to collaborate with Cogentech which is basically a consortium which is partly funded by IFOM and by the European Institute of Oncology which is already developing, has already developed, genetic tests to assess risk for breast cancer.

So we have already the right collaborator that will help us translate the basic findings that we will be dealing with this programme, that we will actually obtain through this research programme, and translate them directly into a clinical setting that could be immediately used in the hospitals.

Are there any other genetic tests soon to become available?

That’s one of the major goals of this programme, namely to extend the list of these few genes that are being currently tested to at least a dozen more.

Some of them, as I said, have been selected on the basis of the fact that there are already drugs that are able to target them.

I’m thinking about, for example, BRAF which is a gene that is commonly mutated in melanoma and in other types of tumours, or ALK in lung cancer and in specific types of blood cancer.

So for those we have now new drugs so it’s very critical to try to now bring the genetic testing from a single test to a higher throughput in order to be able to screen rapidly many patients.

The other important advantage of this programme is, as I said, to move slowly from testing biopsies that we obtain from pathologists through to genetic tests that are being done directly on the plasma, on the blood of the patients, which will have a dramatic impact on the possibility also maybe to isolate early lesions and early events before the tumour is actually diagnosed.

It’s also going to give us a very good outcome of how the patient is responding to the therapy because we will be collecting blood samples at different stages of the treatment and, knowing the type of mutations that we have identified at the beginning we can follow up whether these mutations are disappearing from the blood as a result of the treatment that the patients get.