Stressing prostate cancer to death with drugs shows promise

But first, researchers in London have found that prostate cancer that has become resistant to existing hormone therapies could be treated with an experimental a new drug. It’s called NXP800, it is currently already in clinical trials for ovarian and bile duct cancer, and it works by stressing out cancer cells to the point of killing them. Here’s Adam Sharp, a co-author on the study and leader of the Translational Therapeutics Group at The Institute of Cancer Research in London…

Adam - Over the past 10 to 15 years, we've developed many treatments that can help control prostate cancer and allow men that have advanced disease - that's disease that has spread beyond the prostate - to live for longer. But the biggest challenge we have is that after time, sadly, those treatments stop working because the cancer becomes resistant to them. What it does is it learns ways to overcome the treatments that we're giving to our patients, and it stops working and therefore the cancer continues to grow. In this work, we were really trying to develop new treatments that work through new ways that could maybe help patients that other treatments had stopped working for.

Chris - I suppose it's a bit like when bacteria become resistant to antibiotics, isn't it? It's that they have evolved ways to surmount whatever the blockade imposed by the drug is. How have you attacked this, then? How have you gone after flushing out new avenues that will clog the works up and stop these cancers, even though existing treatments can't?

Adam - The cancer cells are very stressed and they're stressed because they do grow uncontrollably. What that means is the cancer cell needs to protect itself. One way that it does that is it uses a particular family of proteins, the chaperones. They just really protect the cell from that induced stress that the cell is undergoing so that it survives rather than dies. What we did in this study was we actually looked at a drug that had been discovered and developed here, but really tries to stop these chaperones from working and increases the stress that the prostate cancer cell is under. What we wanted to do was to actually decide, if we were to give this drug to our cancer cells, would they be under so much stress that they no longer could survive? Would they either reduce their growth or even die? That's what we really wanted to look at in this study.

Chris - How did you do it?

Adam - My colleague, professor de Bono, has a huge number of patient samples. We first wanted to ask the question, these chaperones, these molecules in the cancer cell, do they make the cancer cell more happy? We actually identified that patients that have more of these chaperones in their cancer cells sadly did worse with current treatments. We then wanted them to take this drug to see whether or not it worked. It's meant to increase the stress or reduce those chaperone proteins that the cell likes to increase the stress. We treated prostate cancer cells in our labs and we also treated many tumours that have come from prostate cancer patient samples, and these specific cancer cell samples were resistant to our current treatments. What was exciting to see was that with this drug, these actual cancer cells started to die. Then what we did following that was we tested it in animal models as well to show similar effects to what we were seeing in the lab cancer cells.

Chris - Effectively you're robbing the cancer cells of a defence they rely on, so they become stressed to the point of toxicity. They just die. But what's to stop them just evolving a defence against the drug so they can switch those defences back on, as it were, and just do what they've already done for the other treatments. Are we just kicking the can down the road a bit here?

Adam - I think that's a really important statement. The challenge, as you've said, is the cancer will evolve ways to overcome resistance to the new drugs that we're also developing. So alongside developing those drugs in themselves, we also now, following from this work, start to look about what drugs we could put the new drug with to maybe overcome the mechanisms of resistance that occur.

Chris - How selective is the drug for prostate cancer cells? Because obviously these proteins that you are robbing the cancer cells of play a really important role in protecting healthy cells as well. Are there not potentially really serious side effects from doing this?

Adam - That's a really important question. The way that we would describe it is actually cancer cells themselves can become more sensitive to these treatments because they have more reliance on those chaperones. A normal cell that isn't as stressed doesn't actually require them as much as a cancer cell. What we hope is that that's what can deliver us the therapeutic window.

Chris - Could this treatment also become a way to make other treatments even more effective? Because when you are treating prostate cancer with, for example, radiation, that's really stressing cells. If you give a drug at the same time, that makes them even more vulnerable. Does that make the power of the radiation the killing effect even more potent and therefore you could get away with say, lower doses, or get an even better response in the cancer so the person has a better outcome?

Adam - Fantastic question, and I think that's what I actually hope more about this paper: not so much our work, but also bringing interest to the field. There has been some great work from other labs that have already shown that increasing the stress response can sensitise to radiotherapy.

Chris - At the moment you've done this in a dish and you've done it in these experimental animals. How close are we now to being able to do clinical trials? Do you foresee this being a relatively easy route into the clinic?

Adam - This work is done in preclinical models in the lab and is exciting, but of course that's still a long way from showing that it works in prostate cancer patients in the clinic. What's exciting is the drug itself has been developed and it's now being given to patients with advanced ovarian cancer and cancer of the upper GI tract, and therefore the clinical trials are already running. What I hope is also exciting enough about this work is that it will make our collaborators in biotech and industry start to think about prostate cancer as another potential indication for this drug.