AACR Annual Meeting 2013

Targeting tumour suppressor genes

Dr Douglas Lowy – National Cancer Institute, Bethesda, USA

http://ecancer.org/conference/350-aacr-annual-meeting-2013/video/1907/targeting-tumour-suppressor-genes.php

Douglas, you’re in an extremely important position looking at basic scientific mechanisms, pathways, within cells at the genetic level. It’s led to this wonderful fact that we have, for instance, things like the HPV vaccine. Could you tell me a little bit about what you’re doing at the moment because you’re working on a tumour suppressor gene, it’s not necessarily got an immediate application, but what kinds of breakthroughs are you getting in terms of understanding?

Well I think, for me, what’s really interesting and exciting is trying to understand the proteins that this tumour suppressor gene protein interacts with and how they regulate this tumour suppressor protein. And in the long run I think there might be some translational implications. One of the serious problems that we have in cancer treatment is almost all of our cancer treatment is directed towards the genes that promote cancer or maintain cancer. And we really have very little that we do that we think about trying to essentially re-establish the activity of tumour suppressor genes. And part one of my goals on a long-term basis is to try to sufficiently understand the interactions between this tumour suppressor gene, the protein that it encodes, and the other proteins that it interacts with so that maybe we could re-activate it relatively specifically as a new way of trying to approach cancer.

Right, and that’s in this case the DLC1 tumour suppressor gene that you’re working on?

That’s right, yes.

What have you found so far?

Well we’ve found thus far that it interacts with two different proteins that are very important in activating integrin. And integrin activation is important for advanced cancer. So we suspect that interfering with the integrin activation might be a way of basically… that this gene works regularly. But more interestingly, I think, in the future is going to be trying to identify interactions with even more potent oncogenes and to try to see if you could re-establish the activity of the tumour suppressor.

What kinds of modulators of these genes could there conceivably be and are you, in fact, looking at at the moment?

Well, there are various kinds of modulators. One is that if the half-life of the protein is short you can think about ways of essentially increasing the half-life of a protein thereby increasing its activity. Another is that if the interaction with another protein turns off this tumour suppressor protein you could think about trying to interfere with that interaction as another way of trying to re-establish its activity.

Of course we’ve been hearing about interfering with cellular processes for years and many of them do work quite dramatically. But at this AACR meeting, here in Washington DC, we’ve been hearing that you could really get to grips with the genome and find out what’s happening in tumours and individualise therapy. On the other hand, we’ve also heard that it’s possible that there are some pan-cancer switches at the genetic level. How is this all looking from your point of view?

Well, my perspective is that in the short term that trying to interfere with these relatively uncommon changes is going to be helpful. But that’s in part because when it comes to the major cancers we aren’t seeing the kind of imatinib story where there is a single problem that occurs with most of the tumours. On the other hand, there are a lot of exceptions and we just have not been very effective at trying to develop inhibitors against those really common genes that we know are important for cancer. So I think that in the long term it’s very important for us to try to target them.

Is there a chance that we could do that? Because one of the matters, it might not be commercially viable to put in all that hard work to get it.

Sure. So one of the projects that the National Cancer Institute is seriously considering initiating is what we call the Ras project because the Ras oncogene is activated in almost all pancreatic cancers, about half of colorectal cancers and about a quarter of lung cancer. So these are very important causes of mortality from cancer. We’ve known about these abnormalities for probably close to thirty years but efforts, both in the private sector, that is by pharmaceutical companies, as well as in the academic sector have thus far not really made the major breakthroughs and we’re hoping that a concerted effort might, over a period of years, actually be able to essentially untie this Gordian knot.

Of course, Richard Nixon wanted to throw money at cancer and beat cancer, didn’t he? It didn’t entirely work overnight. What’s actually holding up this understanding of Ras that’s preventing you from turning it into a druggable feature?

I think that there just… it’s just turned out to be very difficult to target the kinds of proteins that Ras is a member of. It basically acts as a switch and trying to target that switch has turned out to be very challenging. But there are a lot of technological advances that have happened over the last few years and we are…

Computer power, for instance?

And we understand that pharmaceutical companies need to try to develop products that are going to be successful in the short term. And in the academic or government sector we have the luxury, if you will, of being able to have a somewhat longer horizon line and so we’re hoping that by having this concerted effort that we will be able to at least initiate the process that in the long run might then be taken over by the private sector if they see that, yes, there are potential leads that could lead to successful interventions.

Meanwhile, you’ve got some successes under your belt. HPV is one of them, the vaccines.

My own research, yes. But I think that in terms of successes I think that we have a lot of these examples where a relatively small percentage of tumours have actionable changes that permit you to consider and actually show that they work some kind of targeted approaches. The HPV vaccine work that I’ve been involved in really is the outcome of basic research because really basic researchers are the ones who were able to identify HPV as the main cause of cervical cancer first and then as the cause of a number of other cancers, including anal cancers, vulvar and vaginal cancers and head and neck oropharyngeal cancer.

In fact it’s very interesting in the case of head and neck because it has a different effect, HPV, doesn’t it? It can be good or bad.

So what happens is on the one hand the incidence of HPV positive oropharynx cancers has gone up more than threefold in the last 25 years in the United States. On the other hand, the HPV positive oropharynx cancers have a much better prognosis and a much better response to treatment than the HPV negative cancers, largely because the HPV negative cancers are associated with smoking and, for reasons that we don’t fully understand, tend to have a much poorer prognosis.

If you have HPV positive and you smoke what then?

Then you’re sort of intermediate. It’s not as good a prognosis as HPV in non-smokers but not quite as bad as HPV negative in smokers.

Now, how easy was it for you to develop the whole technology for HPV because there are a lot of different HPV variants, aren’t there?

Yes, well I think that the people who developed PCR and made specific primers for HPV are really the people who made the initial breakthroughs for identifying HPV in other kinds of tumours and demonstrating that cervical cancer really is attributable to HPV infection. It really was a technological advance because there were a lot of false negatives and false positives with less specific and sensitive assays. With vaccine development actually there was not much activity in the private sector and the different laboratories that contributed to the technology that led to the development of the FDA approved vaccines were actually all in the academic or government sector and then those advances were licensed by the pharmaceutical companies and developed into the vaccines.

And when you’re talking about head and neck cancer, you could yield a harvest a couple of decades down the line, couldn’t you?

Yes, it will take a long time because one of the disadvantages of cancer vaccines, as opposed to vaccines against acute infections, is that the development of the cancer takes a long time and the cancer vaccines I’m talking about are preventive cancer vaccines, not therapeutic cancer vaccines and so you need to be vaccinated before you get exposed to the infection.

So you basic scientists are picking up the baton in places where industry can’t really do it commercially so easily. Tell me about second generation vaccines, then.

Well, second generation vaccines come in at least two different flavours. I would say the principal goal of second generation vaccines is to try to cover a broader spectrum of the HPV types that cause cervical cancer because the current vaccines target the two most important types which together can target about 70%. But there are about ten other types that together account for the other 30% and so one kind of second generation vaccine, for example, is being developed by one of the pharmaceutical companies, in this case Merck, which adds the next five most common oncogenic HPV types and together, if that vaccine is successful, might be able to protect against about 90%. In our own lab we’re trying to work on a somewhat different approach which is to try to develop a pan-HPV vaccine that might be less expensive to develop and deliver because we can basically target areas of the protein that induce what we call cross-neutralising activity, so it would be protective against a broad spectrum of HPV types.

There are other cancer viruses, aren’t there?

Sure, there are quite a number of others. Certainly hepatitis B, for which we already have a vaccine.

And C.

But there are millions of people who have chronic hepatitis B virus infection and we don’t have good interventions for them. Hepatitis C virus which, again, a lot of chronic infection and the development of vaccine has been lagging but we actually are developing progressively better anti-virals and this is a very good way of intervening and trying to prevent the development of cirrhosis and hepatocellular cancer from hepatitis C virus. And there are other viruses which also cause cancer.

Clearly cancer doctors should take great encouragement from all of this work that’s going on. How would you sum up the relevance of this basic endeavour and the clinical applications that have come out already? What should doctors be thinking about all of this right now?

Well I think that in the long run the basic research that we have carried out, a certain amount of it has come to fruition in having a clinical impact. And, as time goes on, I think it just will be more and more in terms of that. To just give you one example, the BRAF inhibitors that have proven to be quite efficacious, at least on a short-term basis, in melanoma. We understood BRAF because back in the 1980s somebody identified BRAF in a virus, in an oncogenic virus, and figured out what it did. And really that information developed in the ‘80s and ‘90s is what made it possible to go in basically less than ten years from identifying the abnormalities of BRAF in melanoma and having a successful intervention for clinical treatment.

What would you like doctors to be doing about all of your work? Obviously supporting and encouraging it.

I think that they should just… I think that they should stay tuned and they really are the people who are at the forefront because they are the people who are involved in trying to advise their patients, both for prevention, screening as well as for treatment. And we rely on them and being knowledgeable about what the best approaches are.

Well we rely on you to keep us well informed about all of this. Douglas, it’s a pleasure to talk with you, thank you very much.

Thanks so much.