High levels of mutated p53 indicate metastatic phenotype

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Published: 5 May 2014
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Dr Guillermina Lozano - The University of Texas MD Anderson Cancer Center, Houston, USA

Dr Lozano talks to ecancertv at the AACR conference about her work work with the mutated p53 gene.

Her study found that high levels of mutated p53 were at high risk of developing metastases.

By checking for levels of p53, doctors can be better informed of the best chemotherapy treatment options.

Though they have not yet found a way to eradicate this gene, the findings offer a meaningful contribution to personalised medicine. 

 

 

AACR 2014

High levels of mutated p53 indicate metastatic phenotype

Dr Guillermina Lozano - The University of Texas MD Anderson Cancer Center, Houston, USA


Could you tell us about the work you’re doing with ‘gain of function’ in the p53 gene?

Most tumours will inactivate p53 by multiple mechanisms and a very common mechanism is generation of mutations in the p53 gene which result in a protein that has no p53 activities but because the protein is expressed at high levels it has additional activities that result in a metastatic phenotype in our animal models.

Is this different to deletion?

Deletions are uncommon for this tumour suppressor as opposed to other tumour suppressors. So the most common event is the generation of these missense mutations and the hypothesis in the field is that these missense mutations provide the cells with an additional growth advantage and that’s why you see the mutations more often.

Can you tell us more about the protein you found?

We made a mutation in an animal model that mimics a very common mutation in human cancers, in fact it’s called a hotspot mutation. It alters arginine 175 to histidine, that’s the alteration. So we mimicked that alteration in the animal model because now we can study the protein in a physiological system and we can study the genesis and the progression of the tumour phenotype. So what we learned from those studies is that the difference between not having p53 and having this point mutation is a metastatic phenotype.

Does this mean you’ve found out how tumours become metastatic?

We think so. So it is clear that if this protein is present and stable and present at high levels that it will give you a metastatic phenotype, yes.

Isn’t this the holy grail?

It’s just the beginning, I think, because we know that it contributes to the metastatic process but we don’t exactly know how. So the next set of experiments are going to be addressing the question of how it contributes to the metastatic phenotype.

Is this what is known as a phospholipase of mutant p53?

We’ve identified a possible mechanism of how this mutant contributes to metastasis because we know that it upregulates this phospholipase called PLA2G16. So we’ve done a lot of experiments to try to understand how PLA2G16 contributes to the invasion and the migration of the tumour cells.

Is that a transcriptional target?

It is a transcriptional target but it’s an indirect transcriptional target.

How well do you understand this mechanism?

A mutant p53 cannot bind DNA directly because it has a mutation that doesn’t allow it to bind DNA and what we think is happening is we think that it’s being drawn to the DNA by another transcription factor that can bind to DNA. So what happens is this mutant brings in a very potent transcriptional activation domain to a target that normally would not be regulated by p53 and that increases the levels of PLA2G16.

What can an oncologist take from this?

I think what we can say to the oncologists today is that if the tumour has high levels of a mutant p53, our studies say one particular mutant but our studies are also implying that other mutations, other hotspot mutations, will also contribute. So if that patient has high levels of this mutant p53 it is likely that patient will have a metastatic phenotype.

Could this lead to more personalised care?

Absolutely. Physicians are now sequencing the p53 gene in all kinds of cancers. It’s a first step in personalised medicine. I think you have to couple that with the levels of p53 because it’s not just a mutation, it’s also expressing it at very high levels in the tumour that together give you the metastatic phenotype. So, yes, I think it’s the beginning of personalised medicine. What I think the big question now is how do we inhibit that metastasis. We know this mutant p53 will contribute to a metastatic phenotype, we don’t know yet how to stop the metastasis.

Is it not possible to block p53?

We could, we’re trying, but it’s not just blocking p53 it’s getting it out of the picture. It’s eliminating it, eliminating this mutant.

What would be your take-home message?

Know whether your patient has a p53 mutation and know whether it’s present in high levels or not. I would say if both are true then you’d better treat with the best or the most effective chemotherapies that you think are available.