2010 San Antonio Breast Cancer Symposium, 8-12th December, USA
Interview with Professor Paul Workman (The Institute of Cancer Research, Sutton, UK)
Molecular chaperones: cancer dependence and druggability
I was asked to talk about the role of the stress response in cancer and particularly what we call molecular chaperones and how they are important in supporting cancer and also how they can be targeted to produce a new generation of cancer drugs.
What is a molecular chaperone?
Molecular chaperone, first of all it’s a protein, but it’s a molecular machine, it’s required by other proteins in the cell in order for them to adopt the right shape and to be activated by other proteins. So what’s interesting in cancer is it turns out that a large proportion of genes that produce cancer causing proteins, many of these proteins require Hsp90 and particularly when they’re in their mutant forms. So cancer is basically driven by genetic instability, genes get mutated and these mutated genes encode proteins that are less stable than the wild-type protein, the normal protein.
So on the one hand they’re very important for causing cancer but they have this intrinsic liability because they’re activated by mutation they need to be chaperoned or taken care of by other proteins called Hsp90s. So because the tumour cells need Hsp90 more than the normal cells, because they have these mutated proteins, that makes them more vulnerable to an inhibitor if you can block the activity of that chaperone.
How is this done?
The main thing I talked about, which is with respect to drugs that are already in the clinic, it’s the first generation of inhibitors of molecular chaperones. So you could see them as trail blazers for the approach. Hsp90 requires ATP in order for it to do its job. It binds ATP in the same way that kinases, which are already known to be targets, bind ATP. But whereas a kinase takes ATP and puts it onto another protein and in that way activates the other protein, Hsp90 is an ATPase, in other words it breaks down ATP for energy and uses that to change the shape of other proteins. But nevertheless there’s still an ATP binding site, like a cavity in the protein into which ATP fits, exactly like ATP fits into a kinase. And so if you can design a drug that would block that site you can then block the function of the Hsp90.
So the whole field was opened up in the 1990s when it was discovered that some natural products called the geldanamycins, which were already known to have some anti-tumour activity, usually in cells in culture, not drugs but just natural products that had some effect on cancer cells. And it turned out that they worked by blocking Hsp90, some research that was done showed that. And so that established… It’s important in drug development actually to define two things about a molecular target. The first one is to show that it’s really important in cancer and if you block it you’ll have an effect on the growth of cancer, but you also have to establish that the target is druggable, in other words it’s got a cavity or it’s got some kind of structural feature that allows you to make a drug against it, and not all targets have that.
And so it was the discovery of these natural products and showing that they fitted into the cavity of the Hsp90 that led us and other people to first of all work with the natural products and the first of these natural products has begun to show anti-tumour activity, interestingly in breast cancer as well as in melanoma and prostate cancer. So these drugs that are based on the natural product are the first generation of Hsp90 inhibitors. They've shown proof of concept that the approach works and that you can achieve an anti-tumour effect but they’re probably not the perfect drug.
So as well as working with those inhibitors in the lab and contributing to the clinical trials, we set out, a few years ago now, to make some new Hsp90 inhibitors of our own. We ran a high throughput screen to find some small molecule inhibitors and then we partnered the project with a small UK company called Ribo Targets, which turned into another company called Vernalis, and with them we discovered a new class of Hsp90 inhibitors.
So the next part of my talk was to describe how we discovered the second generation of inhibitors and they have been licensed to Novartis now and Novartis have taken the drug that we developed with Vernalis. It’s called NVP-AUY922 and it’s had a phase I trial, it’s just gone into phase II and it’s beginning to show promising activity. So that was the next part of the talk.
First of all I talked about why chaperones are important, then I described how the early natural products led to showing proof of concept and then I moved on to describe how the next generation of small molecules had been designed to make better inhibitors that ultimately, I think, will be quite exciting for the treatment of cancer.
Can you tell us about the Novartis trial?
Well it’s just gone into phase II now and those phase II studies will be in breast cancer, both ERBB2 positive and ER positive breast cancer. It will also go into a trial in gastric cancer where ERBB2 is important. I’ll come back to why ERBB2 especially seems to be critical here. And there’s another set of trials in multiple myeloma. So those are phase II studies, those are going to take several months to complete and then we’ll have a better idea of the activity of these compounds.
So the really interesting thing that I talked about mechanistically in the talk was… One thing I haven’t mentioned yet is that a real strength of a Hsp90 inhibitor is that, in contrast to a lot of the molecularly targeted drugs that we are working with now which block one or two kinases, Hsp90 if you block it will have an effect on multiple cancer causing proteins. I call it a combinatorial approach – it’ll take out multiple pathways at the same time and therefore have a more powerful effect. And that was part of the rationale for going for this target, although when we started doing it everybody thought it would be too toxic. It’s two sides of the coin – if you hit multiple pathways downstream of Hsp90 you might expect it to be more effective but it could also be more toxic. We decided, as an academic group, to take that risk and to check it out.
Now the prediction would be that an Hsp90 inhibitor would have an effect on many types of cancer because of its pleiotropic or combinatorial effect, but what has turned out to be really quite extraordinary is that ERBB2 driven cancers are much more susceptible and that’s because there’s what I called in the lecture a hierarchy of dependency of the different client proteins. Client proteins are the cancer causing proteins that require Hsp90. They’re called clients because they are looked after by, they’re customers of the Hsp90 and so if you treat a cancer cell with an Hsp90 inhibitor and look at how the different client proteins are affected, I forgot to mention that what happens when you inhibit Hsp90 is not just that you fail to correctly assemble the cancer causing protein, it’s actually sent for degradation in the cell by what’s called the proteasomal disposal pathway. And so you cause the disappearance from the cell of these cancer causing proteins.
So if you look at the order in which these cancer causing proteins are affected by an Hsp90 inhibitor, ERBB2 turns out to be the most sensitive client protein. So perhaps it’s not surprising in retrospect now that we know that that it’s ERBB2 positive breast cancer and other ERBB2 driven cancers that turn out to be the most susceptible. The best readout we’ve got from the clinic so far is with one of these early geldanamycin analogues called 17AAG or Tenes(?) B-mycin. In a phase I trial in breast cancer it was only the ERBB2 positive Trustuzamab refractory patients who responded. There was a clear clinical link between having ERBB2 expressed and having regression from being treated with an Hsp90 inhibitor. So that looks like our best target population. At the moment it would be breast cancer patients who are ERBB2 positive or ER positive and who had become refractory to Herceptin and then treatment with an Hsp90 inhibitor will give a response.
Ultimately if the activity holds up you can imagine bringing an Hsp90 inhibitor in earlier into the treatment, say alongside Trustuzamab or alongside Lapatinib to prevent resistance developing. I think that’s an exciting prospect for these drugs.
What about toxicity?
The side effects of the first inhibitors, the actual products that I mentioned, turned out to be mainly liver toxicity. And that turned out to be what we call an off-target effect, it’s related to a chemical structure of the inhibitor rather than to the Hsp90 inhibition itself.
As a class of inhibitors, and I mentioned in the talk there are now sixteen Hsp90 inhibitors in the clinic, we’ve gone in the last ten years from people seeing Hsp90 as a very high risk, probably toxic therapy, to most pharmaceutical companies are now wanting to have an inhibitor in their portfolio. And so because we’ve had several in the clinic, now we can begin to see which are the features of an Hsp90 inhibitor that are common to the class. It looks like fatigue, nausea, gastrointestinal effects are very common. Interestingly, then, what’s happening with some of the recent small molecules is we’re seeing visual disturbance as an effect, night blindness actually. It’s temporary, it’s reversible and it’s not seen as too serious and we don’t really understand what causes that. But predominantly it’s gastrointestinal, nausea and some fatigue. Generally thought of as well tolerated drugs – if they have the activity then these side effects would be seen as quite tolerable.
What was the third part of your talk?
The third part of the talk was to build on what we’ve learned about from Hsp90 itself to see that actually there are a whole range of other possible targets involved in chaperoning cancer causing proteins. Targeting these could lead to a whole generation of new anti-cancer drugs with slightly different properties. Some that would target kinases, some that would target oestrogen, the androgen receptor, and some that would have a higher proportion of apoptosis and ones that would have different side effects and different patient populations to be targeted.
So I really concluded by saying that Hsp90 has opened the door to potentially a whole new generation of cancer drugs for the future.