Αρχική World News Can we grow the treatments of tomorrow? – That Cancer Conversation

Can we grow the treatments of tomorrow? – That Cancer Conversation

Narrator

Hi, welcome to That Cancer Conversation, the new podcast from Cancer Research UK.

Imagine that you have a headache. Now what do you do? Maybe you’re like me, and you’re someone that quickly reaches for aspirin. Take a pill, drink some water, feel a bit better. Once the headache is gone, you have time to think. You start asking questions like “where did that aspirin come from?” The answer of course, being the shops. But before that, like way before the manufacturer is way before even the scientists – where did that aspirin come from? The answer: the cells of a willow tree. I know it sounds strange, but evidence shows that ancient Greeks and Chinese knew that the bark of willow trees could reduce fevers indigenous Americans knew they could ease pain by drinking a tea made from it. For over 2000 years, all the way back to Ancient Sumer, people have known that willow held curative properties. In the 19th century, scientists isolated compounds from willow, hoping to distil its potent curative properties into a more modern medicine. Now one of these compounds was known as salicin. And by the end of the century, it had been used to create one of the most popular medicines of today: acetyl salicylic acid or more commonly, aspirin.  Now, if something as important as aspirin came from a plant, well, what else might there be? Could plan repositories like here, at Royal Botanic Gardens, Kew in London, with its millions of plants and seeds hold the key to discovering the treatments of tomorrow? Dr. Melanie Howes –  researcher in phytochemistry and pharmacognosy here at Kew – certainly thinks so. She and her lab use chemical techniques to try and analyse plants to get an understanding of the science behind their use as medicines to help us find the drugs or tomorrow.

Melanie Howes 

People have been using plants as medicines, or exploring their properties for 1000s of years. And up until the end of the 18th century, people were still using plants in the form of herbal medicines. So these often consisted of either plant material, or plant extracts that contained many different chemicals, the mixture of different chemicals that can occur in plant species. But in the early 19th century, the analgesic morphine was first isolated from the opium poppy. And this actually led to a whole new era of discovering medicines from plants, which involved isolating a single active chemical from the plant rather than using the mixture as people have done before this. And this actually completely revolutionised how people would use plants as sources of medicines and actually gave us the concept of that single active ingredient that we are familiar with pharmaceutical drugs today.

Narrator 

So like Melanie said, This idea was completely revolutionary. In the following years, some of the most well known drugs today were derived. Not content with just giving us morphine, the opium poppy gave us the drug codeine. From the cinchona tree, the anti malarial compound quinine was discovered. Even the coca plant left its mark with the chemical structure of cocaine inspiring the design of some anaesthetics. So many important pharmaceuticals have been taken from plants to treat diseases, ranging from malaria and dementia, to multiple sclerosis and cancer. One notable anti cancer drug is paclitaxel, which is a chemotherapy drug first isolated in 1971. It’s used today and works by stopping cancer cells from separating into two new cells, stopping their growth, but it hasn’t always been smooth sailing for this drug.

Melanie Howes 

So this anti cancer drug was originally extracted from the bark of the Pacific Yew tree. However, many 1000s of trees needed to be killed in order to source enough of the drug for clinical use. So this threatened the species and in fact, the populations of Pacific Yew trees have actually declined by around 30% in the last three generations. So this clearly wasn’t a sustainable solution. So an alternative had to be found. And especially because we know that the chemical structure of Paclitaxel is so complex, that it cannot be synthesised from scratch in the laboratory on a practical scale. So scientists then turn to a closely related species, so they studied the chemistry of the Common Yew tree and actually found that the leaves contained chemicals that were very similar to Paclitaxel. So it was a much more sustainable solution to harvest the leaves and then extract the chemicals, which could then be converted in the laboratory into not only Paclitaxel to increase supplies, but also into other anti cancer drugs such as docetaxel. So this is actually a good example showing that knowledge of plant taxonomy – how plants related to each other – and also plant chemistry can also lead us to finding more sustainable ways to source medicines from nature.

Narrator 

There have been so many different drugs, including anti cancer ones that have been derived from natural world. But have we discovered all that we can? Melanie doesn’t think so and her team at Kew find the drugs of tomorrow and the plants of today. But is it just as simple as pointing at one of the several million plant specimens at Kew Gardens and testing it? Well…not exactly.

Melanie Howes 

Well, there are a number of different ways we can approach selecting plants to study for their medicinal potential. We could just collect many different plant species at random, and then test them for a particular biological activity, hoping that at least one of them would have the required biological or potentially medicinal effect. But we also can select plants in other different ways. So one way is to select plants that have been used traditionally for a particular medicinal purpose. And then we would study those plants to find out if there’s any rational scientific basis to explain that traditional use. And there’s actually a really good example of a drug that was discovered in this way. So that is the study of ethnopharmacology. And there is a plant called Artemisia annua, which is also known as sweet Wormwood, and this has been used in traditional Chinese medicine for 1000s of years, especially for fevers, which can be a symptom of malaria. And in the 1970s, scientific research revealed that this particular plant contained a chemical called artemisinin, which was developed as an anti malarial drug and the scientist who was involved in his discovery and development, she was actually awarded a Nobel Prize in Medicine for this achievement. But at Kew, we’re actually using another approach to select plants. And this is based on the knowledge that medicinal plants and those which are known to be sources of pharmaceutical drugs are not distributed randomly across the plant tree of life, but they tend to occur in cluster patterns. This means if we can understand which plants more closely related to each other, we can then focus on those clusters of plants of high medicinal interest. So this enhances our ability to predict which plant species might be more likely to yield other medicinal compounds. But it can also help us predict which species might be more sustainable sources of them too.

Narrator 

So once they discover the plant that they think might be useful, where do they go from there? Because plants are mixtures of so many different compounds, from the ones involved in producing energy from sunlight to those responsible for controlling how the roots grow. So how do they find a chemical needle in a botanical haystack?

Melanie Howes 

So the process then would be in the laboratory, so this is to understand which of the active constituents. So in the laboratory, the first step we would do would be to usually prepare an extract of a plant. So this would typically involve placing plant material so once we’ve selected our plants, placing the material into a suitable solvent. This could be alcohol or water. So it’s essentially a little bit like making tea. So once we’ve extracted out the chemicals, we then discard that plant material. And this leaves us with an extract that contains can contain hundreds of different chemicals, potentially. In order for us to identify which are the active ones and what they are. We have to purify them. So chromatography is is a laboratory method that enables us to separate out mixtures of chemicals based on their chemical and physical properties. And we then use various analytical techniques to identify what they are. And we can test the original extract, or the groups or fractions of chemicals through this process and the individual isolated chemicals, but for their pharmacological activities,

Narrator 

Melanie and her team are experts at this. But this is a long process. And it’s not always successful. Now, seeing as scientists have been isolating compounds from plants for over two centuries, surely by now, we should have built up enough knowledge to be able to design new drugs in the lab without having to do all this work finding new interesting plants. But it seems that it’s not as easy as that.

Melanie Howes 

I would say actually, that plants are brilliant chemists, and they can produce a diverse array of highly complex chemicals. And many of these plants will produce as a strategy for their own survival. So for example, some plants might produce very potent or biologically active compounds to help to turn predators and protect themselves. And so, throughout history, humans have harnessed the properties of some of these chemicals to develop as pharmaceuticals. So I’ve mentioned a few examples today. But it’s also important to understand that there are certain plant chemicals that are so complex that even today they cannot be synthesised from scratch in the laboratory. So examples of these include the anti cancer drugs and vincristine and vinblastine, which were first isolated from the Madagascar periwinkle plant – so we still rely on the skills of plants as chemists to source these drugs. So really, it can’t be emphasised enough that plant chemicals can produce very diverse and very complex chemicals and without research into plant chemistry, we might not have some of the pharmaceutical drugs that we are using today.

Narrator 

The fact that we still rely on plants like the Madagascar periwinkle plant to create drugs like vincristine as well as vinblastine, I mean that’s really important. Between them, these drugs have been used to treat a wide variety of cancers, from childhood leukaemia to breast, ovarian, lung and bladder cancers. So these are important drugs. Both of them are on the World Health Organization’s model list of essential medicines, and have been used treat people across the globe for 60 years. The Madagascar periwinkle plants being an amazing chemist also comes at a cost. Around 500 kilograms of dried leaves are required to produce just one gram of vinblastine. You can see how that might be a problem sustainability wise. There are drugs today which play huge roles in life saving treatments, but over-harvesting plants could damage ecosystems and affect the indigenous communities who first supplied the knowledge of how to use them. To prevent this from happening, the United Nations set up the Convention on Biological Diversity. It’s been ratified by 196 nations and aims to prevent any threats to biodiversity. So once scientists like Melanie have received plants, isolated the chemicals and tested them for potential anti cancer properties – what comes next? Creating a drug. And no, it’s not as simple as taking those plant extracts and putting them into a pill or injecting them into a patient. These drugs still have to be turned into something more usable. And we have someone who understands this sometimes lengthy process all too well.

Gavin Halbert 

So I am Gavin Halbert. I am the director of the Cancer Research UK formulation unit. And we have a role of taking any new chemical that can be used for the treatment of cancer and converting it into a product that can be safely administered to patients and clinical trial. Everybody will be aware of those types of products because they’re either things like tablets or capsules or injections.

Narrator 

Like Gavin said, they work to create drugs that ends up in patients. But it’s not super simple. So when Melanie’s team extract plant based compounds and show that they have potential anti cancer properties in the lab, what happens next to these compounds? Do they have to be treated in a special way compared to compounds designed synthetically?

Gavin Halbert 

And the simple answer to it is, once we’ve gone through that process and isolated the material from the plant, as a single chemical compound, then from the pharmaceutical perspective in terms of making the drug, it gets treated as any other chemical compound. So we would then, you know, look at the purity of the material, what likely impurities are present based on the way that the material has been extracted from the plant. And then we would look at the stability of the material. So how long can we hang on to it before it degrades, and what we need to do to to convert it into a product. So once you’ve got that compound, from our perspective pharmaceutically, we would treat it the same as you know, a synthetic compound that has had nothing to do with plants.

Narrator 

While this is mostly true, plant derived compounds do sometimes pose particularly difficult issues.

Gavin Halbert 

For a lot of the plant based medicines because they’re coming from plants, they don’t dissolve in water. So plants don’t dissolve in water. Otherwise, yeah, it’d rain and nothing would be green. So they tend not to dissolve in water. So we have the problem that we’ve got to somehow get it to dissolve in water so that we can then safely administer it to the patient in the clinical trial, or just patients in general. I mean, this is that that is why the unit was established. We were established by Cancer Research campaign, way back in the 1990s. Simply because at that point, the oncologists were trying to get drugs into patients. And they were having to try and dissolve the drug at the patient’s bedside. And that wasn’t working. So there are a range of techniques that the chemists can do to modify the molecule to increases solubility. But if you do do that modification, you then have to make sure that once you put the the plant based chemical modified plant based chemical into the patient, it reverts back to the original form that will give you the activity, which usually means that what you do is you make the molecule less stable, but more soluble, which from my perspective, the solubility is good, but the lower stability is bad. So you then have the issue of “oh, I’ve made it soluble, but it’s no longer stable. So I need to sort the chemical stability so they can make the product.” And so what you’ve got to do is to achieve the balance that allows you to optimise the activity in the patient. It is one of these things that is not simple to do is not easy, but usually if you apply the correct science to it – and that is not cancer science, it’s pharmaceutical science – you can solve those problems.

Narrator 

So at this point, a potential anti cancer compound could have been extracted and isolated, it would have then been tested in the lab and sent to scientists like Gavin, to maybe modify it slightly to make sure it takes all of the boxes to be used in clinical trials. So at this point is it as simple as taking this compound and popping it into a pill press or something?

Gavin Halbert 

From a pharmaceutical point of view, we no longer really use pills. But that is it. So the main type of of administration route that we reduces is intravenous injection, some form of injection into the patient, because that actually gets the material into the patient in a known dose in a controlled manner. It’s obviously that patients don’t like that. And I can sympathise with that because you have to go to hospital, you’re going to have to get yourself hooked up to some form of intravenous drip. So it’s not a pleasant experience. So the optimum route, if you can manage it is to use oral administration. So as you will say, the pill press. It’s not as absolute as intravenous administration. So if you took the wrong type of tablet, it could easily come out the other end – everybody knows where that is – without being absorbed. So you have to then when you’re making those types of products, ensure that the drug will be absorbed from the gastrointestinal tract and you will get that activity in the patient that you desire.

Narrator 

Although he’s made it sound quite easy, the act of creating these drugs, it can sometimes be a really difficult process. So just how long does something like this take?

Gavin Halbert 

If you speak to anybody in this field that are sort of, you know, the the simple answer is it takes too long. But the realistic answer is it takes as long as it takes, because at the end of the process, you are going to administer that drug to a patient. And some person is going to be the first person to get that drug. And therefore, you have to do it safely. So you have to take account of all of the required safety procedures. And obviously, we have learned new safety procedures the hard way over a number of years. So it can take a reasonable period of time. And one, one, that one illustration would be that the drugs might not be chemically stable, they might want to degrade. So one of the things that we need to do is to do a stability study on the product before we administered to the patient. And a stability study takes time. Now we have good ways of trying to speed it up by using higher temperatures. But I like to have at least three months data that tells me the drug or the product is not going to degrade before the patient gets it. Otherwise, you know, I will be making a batch of material, it might only have a shelf life of three months, by the time I ship it to the clinical centre, it’s almost expired. So that takes a finite period of time. Lots of the other tests take finite periods of time. And usually what happens is we do these in a linear fashion. So we do one test followed by the next. If we can get the drug as a compound, we would (fingers crossed) like to try and get it into the first patients in under two years. That’s quite a stretch. But if everybody wants a sort of another example, which is very pertinent just now. If you look at the speed at which the COVID vaccines were developed, they realistically were developed in under a year. And that was achieved by not putting these tests in a linear fashion one after the other, but taking a gamble and doing them all at once. And of course, if you take a gamble and do them all at once, then you really need a bigger amount of resource thrown at the problem from day one.

Narrator 

Remember Paclitaxel, the drug that Melanie told us about? It was isolated from the Pacific yew tree in 1971, but only approved for medical use in 1993. That’s 22 years later. But this wasn’t just down to the difficulties of optimising drugs. Because it’s not enough that the plant that it might have been derived from might have been used for 1000s of years, or that the compound itself has seen good anti cancer properties in the lab. No, you have to find out how patients respond to it. And that means it has to go through a clinical trial where patients are given a treatment and assess to see how effective it is and if there are any major side effects.  As we’ve heard, a wide variety of plants can be used to source potential life saving compounds, but a lot of them are plants that most people have never heard about. Professor Susan short is a brain tumour specialist who works at the University of Leeds and St. James’s hospital, treating adult patients with primary brain tumours. She’s been running a clinical trial to see if brain tumours can be traced to a little extra help from compounds derived from a plant that most people know about – cannabis.

Susan Short 

So Sativex is a mixture of two different cannabinoids, cannabidiol and THC. It’s also got some other plant based extracts in it, and it’s manufactured as a spray so patients spray the suspect into their mouth or around their mucous membranes in order to absorb the drug.

Narrator 

But Sativex isn’t new, it’s been used by people with multiple sclerosis to improve symptoms related to muscle stiffness. But in the first clinical trial of its kind, Susan’s team looked at how patients with recurrent glioblastoma could be treated in a new way. They wanted to see if Sativex could be used in combination with chemotherapy

Susan Short 

And we tested that in a small group of patients who have aggressive primary brain tumours that had grown back after standard treatments, so they’ve had surgery. They’ve had radiotherapy and chemotherapy. And when the tumour showed evidence of growing back on scans, we treated them again, with a combination of this Sativex cannabinoid medication and temozolomide, which is one of the conventional chemotherapy drugs that we use for this disease. And that combination is based on some preclinical experimental work that suggested that this cannabinoid drug sensitise the glioma tumour cells to chemotherapy, particularly to chemotherapy with temozolomide. So, we thought that that combination may be effective in these patients. As I said, it was a small study and the main purpose of this study was to make sure that the combination of the temozolomide chemotherapy and the Sativex, the cannabinoid, was safe to give to these patients. And we found that, in general, it was. There were on patients who got some side effects, particularly tiredness. There was some patients who got dizziness and sickness and some patients had to stop treatment because of side effects. But the majority of them managed the treatment relatively well. So that’s what we’ve reported. We also looked at how these patients did, how long they survived after treatment. And although this was a very small patient group, some of the patients did seem to do better than we would expect. We did for part of the study we randomised patients to either receive the cannabinoid medication itself or a dummy, so a placebo equivalent. And it did look as though the patients who got the active drug did better.

Narrator 

So it’s really important to try to understand exactly how these treatments are working inside the body. As cannabinoid research is still relatively infant, do scientists well and truly understand the effects of them on the cancer cells, especially in this case when the chemotherapy drugs involved?

Susan Short 

So it looks as though the combination really pushes the cells into a sort of stress response. That means that they’re more likely to die after being exposed to the chemotherapy, so the combination works much better than either on their own. All the details of how cannabinoids work, certainly in brain, is quite a complex signalling system but one thing that we do know is that the receptor proteins on cell surfaces that respond to cannabinoids are present in very high levels in a lot of glioma cells. So in a lot of these brain tumour cells, that suggests these tumour cells are specifically sensitive and prepared for signalling from these cannabinoids. And that goes along with the fact that in preclinical experiments, so in experiments done in the lab, the models seem to respond to cannabinoids in that you can reduce the tumour cell growth when you when you treat cells or animal models with these tumours with cannabinoids. So it’s the fact that we know that the relevant receptors are there in high levels. And in the lab, these cannabinoids do seem to act as anti tumour growth drugs. So that’s really what has made them interesting in this in this context.

Narrator 

So one of the big things that you hear online is that cannabis cures cancer or that organisations are intentionally suppressing the research. Susan’s work is looking at compounds derived from cannabis but she’s quick to point out Sativex and cannabis are not the same thing.

Susan Short 

There are lots and lots of different and cannabinoids. This Sativex medication is combination of two main ones but you know some other concentrations of minor cannabinoids, you really you can’t you can’t describe it as cannabis. You can’t. It’s not the same thing. You know, cannabis itself is a very nonspecific term. The issue around this study is all about “well why can’t I just go and buysome cannabis oil or, you know, buy a cannabinoid and take that and shouldn’t I be doing that anyway?”  And the answer to that is definitely no, because we don’t know was in a lot of those. Especially the over the counter medications. There’s probably not very much active drug and we don’t want people leaping to conclusions before we’ve done the definitive study, which we were trying to do as soon as we can, so that we get this answer back. It seems like a really appealing idea, that you could just go and get a cannabinoid preparation and take it and it would be really easy to treat your horrible aggressive brain tumour. But actually, we have very little evidence that that’s really the case.

Narrator 

When it comes to clinical trials, there are multiple phases, and this was just the first in many of them but Susan’s team are not stopping there. While it might seem that they could just test Sativex with every different type of cancer, they want to understand it a little bit more, they want to really delve into how the drug works in people with glioblastoma on a much larger scale.

Susan Short 

So we don’t have any plans to look at other tumour types at the moment, but I think it might well be the case, particularly if we find that there’s any promise in this treatment for patients with glioblastoma, that we look at other patients with different brain tumours. We would also want to ex[;pre whether same the same effects occur in them. We are in the process of planning a bigger study. As I said, the study that we’ve recently reported was far too small to be able to give us any confidence that we could answer a question whether this drug was useful in patients with recurrent glioblastoma. So we need a much bigger study that includes, you know, hundreds of patients rather than 20 something patients and we’re in the process of planning that now. And so we hope that that study will be available for patients across the UK sometime in the next year or so.

Narrator 

Thanks to the promising results seen in this – the world’s first trial with Sativex to treat glioblastoma – they’re now continuing their work with the next stage of the trial, which is known as ARISTOCRAT, which hopes to recruit over 230 patients across the UK starting next year 2022.  This has been That Cancer Conversation we were produced in Cancer Research UK’s digital news team. And our music today came from Poddington Bear. To learn more about the trial, you can find a link to the University of Leeds page along with various other reading in the show notes. To be the first to listen to our next episode, you can subscribe on Spotify, Apple podcasts and wherever you get your podcasts. Thanks for listening. We’ll see you next time.

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