Targeted therapies for colorectal cancer

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Published: 21 Nov 2012
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Dr Alberto Bardelli – IFOM – University of Turin-Medical School, Italy

Dr Bardelli explains that with research now creating a total picture of the genetic mutations for colorectal tumours, there is a move to use this to create new, targeted therapies.


While the main approach is still chemotherapy, there are hundreds of new agents undergoing clinical trials, as well as analyisis of individual tumours in a laboratory setting.

Why are you working on colorectal cancer?

I did my postdoctoral fellowship at Johns Hopkins with Bert Vogelstein which, as you know, is probably the father of cancer genetics and certainly of colorectal cancer genetics. So Bert got me really interested into the genetic basis of colon tumours and ever since I’ve been working on this fantastic model which allows us to understand for the first time the basis of personalised medicine I believe. The progression of colorectal tumours has been defined so well at the histological level and we now know so much about the genetics that we have a complete picture of the mutational profile of this tumour. What we and many others have been able to do in the last five years is to relate this data to the response to therapy which I find extremely exciting, especially because we can now perform what we overall call precision medicine, I believe in.

The main therapeutic approach remains chemo, as you know, but new agents have been introduced, many, many more are in the pipeline, I would say in the hundreds, so we have hundreds of new agents that are ready to enter. What we study is precisely targeted therapies, so a new approach which involves understanding the molecular basis of an individual tumour and identifying a specific drug when it is available to target a specific tumour and therefore that specific patient. This is highly innovative and in fact what we have discovered is that while the chemotherapeutic approach typically applies to all patients and has an efficacy in most patients these new approaches instead have a profound effect in very few patients. For a while it has been very difficult to understand why that would be and we now know why – because each tumour is different essentially.

Do you have a lab model for combination targeted treatments?

Yes indeed and that’s an incredibly good point. So we have very few evidence in which single agent targeted therapies work, we do have some, but the characteristics of these approaches have been that even if the therapy is immediately effective after a few months there is a relapse and the relapse involves all patients. So we and many others are now thinking that… trying to understand why this relapse occurs. And we now know why – it occurs because the mass, which is often a metastasis, is already embedded with many, many alterations that are simply selected for by the therapy. So what we do with these new targeted therapies is to have a profound effect but now immediately resistance emerges. How do go by and how do we bypass resistance? That’s exactly what you said – probably we should start off not with single agents but with combinatorial therapies. I’d like to make one example, which is an incredibly important example, is the therapy not of colorectal tumours but of melanoma in which recent results suggest that by initiating immediately a combinatorial therapy, targeting two steps of the pathway, we delay the onset of resistance. Like you said, we have multiple models in our lab but in Turin and here at IFOM we are exploring together to see whether by starting very early a combinatorial therapy then we can prolong the effect and possibly prevent the onset of resistance.

The latest excitement that we has been in new ways to anticipate resistance. So we know it will inevitably occur and we now detect it in the hospitals with a examination, for example, we have to see the tumour enlarge. Very often that is too late so what we have done is to have the data from the genetics that establish the molecular mechanism of resistance and see whether we can find the single alteration that is responsible for resistance early on. How? We have established a new test which is based on blood. So what we can do now, and what I think and I anticipate will be the future of targeted therapies, is to monitor patients real time in the blood. Why? Because tumours shed DNA and if the tumour sheds DNA it means it sheds also the mutant DNA and the mutant DNA is incredibly specific. What we recently reported in Nature is that if we apply sensitive technologies to blood from patients that undergo therapies we can follow them and very early on, ten months earlier we have shown recently, detect the mechanism of resistance. Then what you just said can be applied, we can start combinatorial treatment very early on.

Are these biomarkers from the blood?

That’s right. What we have seen is that new technologies will allow us to detect one mutant allele in ten thousand wildtype alleles. It means that we can now do what we call a liquid biopsy. We can predict and identify the mechanism of resistance by a non-invasive test, by simply taking blood from the patient.