22nd European Association for Cancer Research, Barcelona, 8th July 2012
Potential for micro-RNA based cancer treatments
Professor Carlo Croce – Ohio State University, Columbus, USA
We’re here at the EACR in Barcelona and Dr Croce, you have just been awarded the Anthony Dipple Prize for your work with micro-RNAs in cancer. Can you tell us a little bit about your presentation today?
As you know, several years ago, in fact ten years ago, we discovered the involvement of this new class of gene in leukaemia called chronic lymphocytic leukaemia and then we went on to show that in fact this family of genes, micro-RNA genes, are dis-regulated in all human cancers and contribute to the pathogenesis of every tumour. We can take advantage of the involvement of micro-RNA in cancer for a better diagnostics, prognosis, monitoring and possibly in the near future we might be able to treat human cancer with a micro-RNA or an anti-micro-RNA.
So micro-RNAs sequester messenger RNAs is that how it works?
No, what they do, they interact with messenger RNA and when they interact with messenger RNA two things happen at the same time, that is the BRCA translation and some degree of degradation. So they regulate their own gene expression and if they are very high they will affect the level, the level of the messenger RNA will be low or the messenger RNA will not be translated into proteins. If the micro-RNAs are lost the expression of the messenger RNA will be high and the messenger RNA will not be inhibited in this translation so you will have high levels of expression of the protein present.
So they work not only on tumour suppressors but also on…?
Exactly, so they affect over 50% of the genes, over 50%, including oncogene and tumour suppressor gene. So when micro-RNAs that target an oncogene are lost, the level of the expression of the oncogene is high so that contributes to cancer. When the micro-RNAs that target tumour suppressor are high, they shut down the tumour suppressor and that can contribute to cancer pathogenesis too.
So when you have a cancer cell lots of things are messed up. And is it now sure that the micro-RNA is a causative agent?
It’s a question of chicken and egg because the pathways that are involved in cancer pathogenesis, they all regulate micro-RNA. The function of the pathway is, at least in part, to regulate micro-RNA so in every cancer there is dis-regulation of micro-RNA. That contributes to cancer pathogenesis. What we can start thinking now is to use micro-RNAs that are lost or anti-micro-RNAs that are over-expressed to treat the human cancer because they are the downstream target of the pathway that is responsible for cancer. So perhaps we can use the micro-RNAs themselves or an anti-micro-RNA to treat cancers that are due to mutations in some major pathways.
So are there any examples?
Not yet but there will be. Before you bring new molecules to therapy there are a lot of regulatory processes. In addition, as everybody is concerned about possible side effects then we are also concerned about the possible side effects because they interact with a lot of genes. But the fact is that in an experiment done in my lab, and many other laboratories around the world, where we use micro-RNAs or anti-micro-RNAs for therapeutics in mice or rats the micro-RNAs don’t show significant side effects. Probably there are reasons for that, why we don’t see side effects.
So these are good reasons that will allow you to go into…?
There are very good reasons why we do not see side effects. One, that micro-RNAs are in general redundant and another reason is that micro-RNAs never shut down the target completely. So a normal cell can retain 10, 20, 40% of the level of expression of the gene that they need but a cancer cell is dependent on that change so the cancer cell is particularly sensitive since it depends on those changes, it’s particularly sensitive to changes that cause malignancy. So if you introduce a micro-RNA that functions as a suppressor or an anti-micro-RNA and you change the target, even by 40, 50, 60%, the cancer cell dies. So I think that would not cause significant side effects.
So looking ahead, when do you think there may be…?
We will try hepatocellular carcinoma because it’s an incurable disease and you have a spontaneous target. So we are now doing toxicity studies of anti-Mir 221 in monkeys. After this we will start the clinical trials of anti-Mir 221 in liver cancer.
We’ll follow you and let’s see what happens in the next few years.
I think that we will get into a clinical trial by the end of this year, so by next year we should have some new data.
OK, thank you.