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A rational new approach to cancer treatment

Published on 06/09/18 at 11:55am

Researchers at the University of East Anglia have developed a new targeted cancer therapy which utilises nanoparticles to deliver treatment directly into tumours. Dmitry Pshezhetskiy (pictured), lead researcher of the project, discusses why the therapy, if successful, could become a new gold standard.

What led to the University of East Anglia pursuing this unique kind of cancer therapy given the current treatment climate for the disease?

For more than ten years now, we’ve been looking for mechanisms for cancer cure resistance. There are plenty of mechanisms, but we identified one which was particularly important in prostate and breast cancers which is through the enzyme sphingosine kinase 1 . This enzyme is overexpressed in prostate and breast cancers, particularly in the ones with aggressive or resistant cancers. Its high expression makes the cell more resistant to chemotherapy; essentially the enzyme’s expression makes the cell tougher. They grow faster and they can survive experiences that other cells can’t survive. They’re a bit like Frankenstein-type monsters.

However, there is one drug which can be used in humans and which is an inhibitor of the enzyme, called fingolimod. The drug is actually a very successful multiple sclerosis drug but it cannot be used in its clear form in cancer patients since it causes lymphopenia and depletes the blood from white cells. That’s how it works in multiple sclerosis. In a cancer patient that would be fatal, as they’d already be compromised.

Nevertheless, on its own it’s actually not a very important cancer drug; the problem is that you need something more than that to treat cancer cells. So we devised a therapy consisting of two parts: fingolimod, which lowers the defences, and the other is a stem chemotherapy called docetaxel which is a therapy given to prostate and breast cancer patients. Both on their own are not particularly effective, but together they show a synergy – one lowers the defences and the other strikes. However, one without the other is not effective.

Because you can’t give the drugs on their own, we said ‘why don’t we give it in a nanoparticle?’ So that’s how the whole concept of giving a combination of two different drugs in a nanoparticle was born. The nanoparticle on its own brings some therapeutic utility due to the fact that their size means that, while they are able to enter into the tumour, they cannot escape from the blood vessel. This prevents them from going into the liver, spleen and kidneys for example, and this is obviously useful because you’re not wasting your drug elsewhere.

How prevalent is nanoparticle delivery technology currently in cancer therapies?

There are seven nanoparticle therapies that are licensed in the world: five nanoparticle therapies licensed in the US and only two in Europe.  However, all of those therapies that are licensed are nothing more than standard chemotherapy treatments, enveloped in the nanoparticle for better delivery and to minimise toxicity. Thus, as of yet no one is utilising the combination therapy that we are using. That is putting two drugs in the same particle, although it is already known that nanoparticles can deliver the treatments to the tumours more effectively.

As all components of the therapy are already approved for use, what does this mean for accessibility of the treatment, should development go smoothly?

It would mean that the finalisation of validation in human use will be a quicker process than the validation would be for a completely new drug. That is a great advantage as it means we can do it quite quickly. In essence it means that we could push this through to the phase one trials in a much quicker period of time.

What efficacy has it shown so far in animal models, and in what cancer types?

We have tested the therapy in two cancer types: metastatic prostate, and metastatic breast cancer. These are human cancers that are bred in mice. Essentially these are immunocompromised mice into which we inject the human cancer cells, and a hybrid model of a human tumour then grows inside the animal. We showed that in both the model of prostate and the model of breast cancer, these therapies were significantly more efficacious than docetaxel; alone. Significantly, docetaxel is a gold standard therapy which can be given to patients with prostate and breast cancer, so of course the combination therapy is more efficacious than chemotherapy alone and equally it showed significantly fewer side effects. So that’s the take-home message as we move towards Phase 1.

How would you describe the biggest advantages of this treatment compared to previous, more traditional efforts?

Basically it’s a very rational approach. We found what made the tumours resistant, then we found a drug which can make them less resistant, and then we found out how to use those to drugs in combination to help cancer patients. So while we did not really use any particularly novel nanoparticles, the whole combination itself is where the innovation lies – you find the target and then you find out how to deal with it.

This is why I believe that if it passes Phase 3, it’s going to be the next state-of-the-art treatment. It’s going to become a gold standard. In essence if you offer nearly any cancer patient a choice of therapies between one which would cause them side-effects and one that wouldn’t – even if you assume that both options have the same efficacy – not a single patient would choose the treatment that would cause them additional side effects. This is especially significant considering that those chemotherapy-type drugs are generally quite toxic. While we all know about the diarrhoea, vomiting and hair loss – these are not the most horrible side effects. The most horrible are the permanent damage to lungs and liver for example, or sepsis. Any patient who receives chemotherapy is at risk of developing sepsis since their immune system is wiped out, and that is what we’re trying to alleviate using the carrier systems.

Using nanoparticles we can thus take the drugs that cannot be used in cancer patients because of the side-effects and we can actually make them usable in cancer patients, which is a great advantage because if you can then target particular parts of the cancer cells and make them less resistant and make them prone to cancer therapies, that’s a great advantage.

So is it likely that this treatment could become a gold standard?

I think it could, because if we can provide patients with higher efficacy and in turn give them more years while also helping to increase their quality of life by removing the side-effects from major therapies, I think that would be a major breakthrough. I don’t think any currently-used therapies would be used after that. However, there’s a lot testing that needs to be done before that point.

What challenges do you foresee in the long development process ahead?

The most important challenge is the fact that both of the drugs have never been given in combination in humans. As of now we have only tested it in mice and while the mice did not react in any particularly bad way, the combination needs further testing in both mice and rodents’ systems before it can be given to humans – that’s the first main challenge to overcome. However, the good thing about the drugs is we know the doses in humans and we know safe doses. So that will simplify the process. However, because they haven’t been given in combination, we’ll have to approach that with caution. So if they pass the Phase 1 studies and we see a better response in some of those stations then I think we’ll probably have quite an optimistic perspective.

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