AACR Annual Meeting 2013

Myc inhibition in pre-clinical mouse models

Dr Laura Soucek – Vall d’Hebron Institute of Oncology

You’ve been working on Myc

For a long time.

The well-known factor causing cancer, but Myc inhibition as well.

Yes

Tell me what you’ve been doing because you had quite a dramatic instance of this working in a mouse initially, didn’t you? Could you tell me what you did?

Yes, we managed to show that Myc inhibition is feasible in animals. There was this fear that inhibiting Myc would cause terrible side effects to normal tissues because Myc is really central in a lot of aspects of physiology of a cell. So everybody expected that inhibiting Myc would cause catastrophic side effects. Instead, what we managed to show for the first time was that systemic Myc inhibition is very, very effective as a therapy against cancer but it doesn’t cause these terrible side effects that everybody was expecting.

And you used transgenic mice to do that?

Yes.

What did you do?

We placed Omomyc as a gene inside the mouse in a switchable manner. We can turn on and off Omomyc.

Omomyc is the actual part of Myc that…?

Omomyc is a Myc mutant that I designed a long time ago when I was an undergrad student still in Italy and it works as a very efficient Myc inhibitor. It sequesters Myc away from its target genes on the DNA. So we placed Omomyc, this dominant negative, in the mouse and we can turn on and off Omomyc by just administering doxycycline to the drinking water of the animals.

So that then was proof of principle that you can mess about with Myc and not get into trouble?

Yes, absolutely. Yes, and the effect on tumours was stunning. That was first done in a mouse model of lung cancer and what we saw was that the lung tumours disappeared very, very quickly while the normal tissues stayed perfectly healthy. The side effects were very minimal and well-tolerated.

Can you just remind me of which cancers and in what way Myc is involved? Because it is quite broad, isn’t it?

Myc is actually involved in the majority of human cancers. What we think is that inhibiting Myc will be a therapeutic strategy possibly for every kind of cancer.

And to take this proof of principle further, you’ve now been working on patient samples with gliomas. What did you do there?

We decided to challenge Omomyc, our Myc inhibitor, with the most difficult cancers to cure. Glioma is in huge need of new therapy. Patients with glioma usually don’t have many therapeutic options, even surgery is often not an option for them because glioma is very, very invasive. And it has been shown that Myc expression levels are correlated with glioma grade so the more aggressive the tumour, the more Myc is there. So we thought it was the perfect chance for us to test Myc inhibition as a therapeutic strategy.

What did you do and what happened?

We used a mouse model that developed, so a mouse that developed glioma and we introduced Omomyc there, our switchable Omomyc. First we saw that we can prevent the development of glioma in these mice. Second, if the glioma is already there, so if we wait for the tumour to develop and then we intervene with Omomyc, the tumours disappear. So Myc inhibition causes regression of these tumours, immediate relief for the mice. The mice usually develop neurological symptoms, very severe neurological symptoms, all these symptoms disappear as a consequence of Myc inhibition. But we didn’t stop at the mice, we decided to test Myc inhibition also in patient derived tumour samples. So we can get tumours from patients that are there in the hospital at the Vall d’Hebron Institute of Oncology and we could test for the first time Myc inhibition in these tumour samples. And even there, in human tumours, Myc inhibition is a very, very effective therapeutic strategy.

What needs to be done now then to actually bring this closer to use in patients?

At the moment there is no Myc inhibitor available in the clinic. So what we are really trying hard to do is to develop an anti-Myc drug.

How do you make your Omomyc?

Omomyc was a Myc mutant that I designed, again a long time ago. It’s a part of Myc, it’s only a portion of Myc in which I introduce very small point mutations. These point mutations allow Omomyc to sequester Myc and bring it away from its target genes.

And you keep it in a bottle?

No! Well actually no. Omomyc has a long history because I put Omomyc in bacteria first, then in cells, then in mice, now in tumour samples from patients.

So how easy is it to put in a form that you could potentially administer?

This is the new challenge for all of us but we have huge hope because until now nobody thought that Myc inhibition was even doable, was even something that could be done. With Omomyc we proved that that can be done so we are trying to design a drug that could do the same thing that Omomyc does.

It would be a wonderful thing to have a magical cure for cancer. What, however, do you think cancer doctors should make of these exciting discoveries?

Well what I hope these studies prove is that we all have to work together to find a drug. So, of course, for doctors this gives new hope for new therapies which hopefully will become available to the patients as soon as possible. Again we are trying to provide new hope to doctors and patients at the moment.

And we’re hearing at this meeting of the AACR, here in Washington DC, that there’s a huge amount of benefit from looking at the genes and seeing how different parts of the genes affect cancer and affect, potentially, cancer treatment. Do you think this gives hope that we can understand this complex situation and perhaps really switch off many cancers?

This is actually a slightly different approach. So for a long time we have proceeded towards personalised medicine. And so we design different therapies according to the mutation that caused the cancer. Myc inhibition gives a different opportunity; Myc inhibition could be downstream. All these variants, all these mutations that can cause cancer, it could be a common conduit for all these mutations to drive cancer. So Myc inhibition wouldn’t be limited to certain types of tumours, it would be a general cure for possibly all sorts of cancers.

So what do you think is the take home message coming out of this at this admittedly exciting but preliminary period of time?

Again, I think that this is hope. It’s hope for a lot of people and it’s huge encouragement to everybody that is trying to find the proper Myc inhibitors to keep going because Myc inhibition could be a very, very effective therapeutic strategy.