ASH 2015

Overcoming the barriers of the P53 dysfunction to cure blood cancers

Dr Guillermina Lozano - MD Anderson Cancer Center, Houston, USA

P53, that’s a massive concept; it seems to be around almost everywhere being involved with cancer. Can you tell me what it was that particularly interested you in hematologic malignancies because I believe it’s quite common, changes in p53 are quite common aren’t they?

Changes in p53 are common in all cancers and it’s these mutations or other mechanisms that cause inactivation of the p53 pathway that lead to hematologic malignancies and other cancers. So we’re just intrigued at trying to understand how these mutations contribute to tumours.

Now p53 is a tumour suppressor gene.

Correct.

It can get deleted or it can get mutated. What’s the difference and what does it matter?

p53 is a potent tumour suppressor and many tumours delete the p53 which just takes p53 out of the picture and those tumours evolve a certain profile. But p53 missense mutations are much more common than deletion of p53 and these are missense mutations that cripple p53 but they also give p53 additional activities and those lead to tumours that are much more aggressive.

So missense means they still have function and it might be a function you don’t want.

Exactly. They don’t have the tumour suppressor function but they have a function that is worse for the tumour.

Here at the American Society of Haematology you’ve been in a session looking at overcoming the barriers of p53 dysfunction to cure blood cancers. What kind of concept can you offer doctors in that quest?

I think the most important concept I can provide is that a tumour that has lost p53 or deleted p53 is very different from a tumour that has a mutation in p53. These tumours evolve very, very differently. So in tumours that have no p53 you somehow have to reintroduce p53 to get that cell from stopping but in tumours that have mutant p53 we and others have data now that says the cell is addicted to having that mutant p53 so the mechanism by which you treat that tumour is going to be very different from how you treat a tumour that has deleted the p53 gene.

Now it would be great to have treatments but you actually have done some work already in a model system that’s giving you some insights into how you might approach this treatment-wise.

A number of years ago we made the models where we can express some of these p53 mutations in a tissue specific and time dependent manner. So the comparison is basically what told us that it’s much worse to have these p53 mutations.

What did you do in the study that you’ve been doing with mice?

We basically can manipulate the mouse genome and we can make the same kinds of mutations that occur in haematopoietic tumours in the mouse and then study what happens to those tumours, how aggressive they are and what happens, how they evolve.

In cancer therapy we hear an awful lot about targeted treatments, about molecular approaches, what does p53 have to offer, then, that might be harnessed in the clinic?

Critical is understanding how the p53 pathway is inactivated.

And how is it?

We’ve talked about deletions, we’ve talked about mutations that lead to more aggressive cancers, but there’s also over-expression of an inhibitor called MDM2. So when MDM2 is over-expressed at high levels you don’t see mutations in p53. There are some clinical studies in haematopoietic tumours that are basically disrupting the interaction of a normal p53 with this inhibitor and those are in clinical trials right now.

What sorts of leads are there, then, for identifying druggable targets for example?

We know a lot of the components of the p53 pathway in general. Where the field has to go now is understanding in haematopoietic cancers which of those components are involved because there are tissue-specific differences. The way a haematopoietic tumour evolves is very different from the way a breast tumour evolves. So we know what all the components are, we now have to narrow it down and see in the specific cancers which of the components are messed up.

So what should doctors then be making of all of this emerging knowledge of p53 and its mechanisms?

I think the first and most important thing that cancer doctors have to do is to understand how the pathway is inactivated in the tumour that they’re studying because how it’s inactivated is going to determine what treatment options the patient has.

And then what kind of hopes might they have for harnessing p53 to cure patients in the future, do you think?

One idea is to take that mutation in p53 out of the picture so that the tumour implodes. Another scenario is to reactivate that p53 somehow and there are some drugs now that people are working on that will take a mutant p53 and make it normal. So those are the kinds of things that are happening right now in the field.

And the take-home message for scientists and doctors at the moment in this very fascinating area of research is what?

Is understand the pathway in your specific tumour because that’s going to tell you how to treat the patient.