Tag: cancer research

What is CAR-T therapy and why did NICE recommend against it?

You might have seen in the news today that NICE has denied patients access to a ‘pioneering’, ‘breakthrough’, ‘revolutionary’ treatment.

But what actually is this treatment?

CAR-T

CAR-T therapy is a type of immunotherapy that takes advantage of the cell killing capabilities of cytotoxic T cells. This particular type of T cell is an important part of the human immune system which for many years, researchers have hoped might be useful in treating cancer.

Cytotoxic T cells surround a cancer cell
Cytotoxic T cells surround a cancer cell (taken from NIH)

The problem is, cancer cells are derived from your own cells so your immune system has no reason to target them for destruction. That’s where CAR-T therapy comes in. In CAR-T therapy, the T cells of the patient are taken from the blood and genetically modified so they express a chimeric antigen receptor (CAR). A CAR is basically a signalling molecule on the surface of the T cells that allow them to recognise cancer cells as worthy of destruction. These genetically modified T cells are then put back into the patient’s blood to target and kill cancer cells.

Because we know that different types of cancer typically have different types of signalling molecule on their surface, we can then use different types of CARs to help draw the cell killing T cells to the cancer cells. For example – nearly all types of B cell acute lymphoblastic leukaemia (ALL) have a protein called CD19 on the surface of cells so researchers have been working on CARs that specifically target cells which have CD19 on them.

B cell lymphoma cell is recognised by a T cell which has a CAR protein expressed on it
Modified from here.

Yescarta

The specific therapy that NICE has reported on this week is one called Yescarta from a company called Kite Pharma. Yescarta consists of taking T cells from the patient then using a system hijacked from retroviruses to genetically modify the cells. The genetically modified cells are then reintroduced to the patient in a single dose.

Clinical Trials of Yescarta have been initially promising. A phase II single-arm trial found that of 101 patients treated with Yescarta, 54% had a complete response and 52% survived over 18 months. All of these patients had refractory large B-cell lymphoma – that means they had a type of blood cancer that had already failed treatment and the patients had an average expected life expectancy of 3-4 months. While the trial showed that all patients had significant adverse events related to Yescarta, only 3% of patients died from the treatment itself.

Yescarta logo

Based largely on this trial the FDA approved Yescarta for certain types of lymphoma late last year and the European Commission granted Marketing Authorisation for the treatment this month.

Why not recommend it?

But NICE had some concerns. Firstly, they were concerned that the clinical trials for Yescarta, while promising, were insufficient to allow recommendation of the drug. While this particular type of lymphoma doesn’t have a standard therapy, yet, most patients are treated with scavenger chemotherapy and the Yescarta clinical trials haven’t proven that Yescarta is better than scavenger chemotherapy. The two therapies haven’t been compared side by side. This is quite a significant concern because, without side by side comparison, we can’t be sure that diverting patients from one treatment type to the other is actually beneficial for the health and life expectancy of those patients.

NICE aren’t saying no to Yescarta, they’re saying “not yet”.

The second concern NICE has is that the treatment is currently very expensive. The cost to the UK has not been made available, but in the US the treatment can cost $373,000 per patient. And this is something that NICE has to weigh up in its cost-benefit analysis. So far, Yescarta has been shown to prolong life by approximately 14 months in around 50% of patients. Is it justifiable to divert so many funds to a treatment that only works 50% of the time and we can only say extends life by a year (so far)?

A woman standing at a laboratory bench facing away from the camera and wearing a lab coat

The company that makes Kite Pharma was bought by Gilead Sciences last year, just two months before Yescarta was approved by the FDA. Last year Gilead Sciences had a revenue of $30.4 billion and a free cash flow of $15.9 billion. Gilead Sciences spent $12 billion in order to acquire Kite Pharma and its marketable therapy Yescarta. NICE perhaps has reason to be cautious.

Any other concerns?

If Yescarta were approved for the use in the UK, it would be the first of its type to be approved. There are potential concerns we need to consider when introducing both genetically modified cells into patients and playing around with the immune system in patients. In his article for McGill, Jonathan Jarry pointed out that “Autoimmunity is when our immune system improperly responds to something that belongs to us” and in the case of Yescarta we’re actively training the T cells to recognise cancer cells derived from our own cells. In fact CD19 isn’t just expressed on cancerous B cells, it’s found on all B cells – even the healthy ones. In the case of terminal cancer this might be a price worth paying but it has to be taken into consideration. Sudden activation of T cells in the body is such a strong response that patients can get very sick and even die from a condition called cytotoxic release syndrome.

We must also consider the reproducibility of the initially promising clinical trials. There is evidence that when repeated, less than 50% of clinical trial results are reproducible and many negative clinical trials go entirely unpublished which means a high likelihood of false positives, it seems prudent to take care when making decisions based on single clinical trials.

Conclusion

NICE - national institute for health and clinical excellence logo

While many patients were hoping for the approval of Yescarta by NICE, the limitations have proved too high at this stage. I don’t think this decision should be used to criticise NICE or the NHS, rather to encourage further research using reliable controls and a focus on bringing down the prices of promising new treatments. It also highlights an example where the novelty of new treatments can overtake scientific sense and lead to approving treatments which might currently be lacking sufficient clinical evidence supporting their use.

Meanwhile, the NHS will not withdraw funding for any patients already undergoing Yescarta therapy and will reconsider their decision given further research or reduced costs.

 

 

Is Cannabis a Cure-all?

You might have seen in the media lately a lot of coverage about the use of cannabis to treat epilepsy and other conditions. It all started with the case of a young boy with severe epilepsy who was using cannabis oil to manage his seizures, with apparently great effect. Until, that is, his mother was unable to bring his treatment into the UK and his medication was seized at the airport.

These stories raise three questions:

  • What does UK law regulate in the case of medications based on cannabis
  • What is a cannabis oil?
  • Can cannabis treat any medical condition?

UK Law

In the UK, cannabis is a Class B drug – you aren’t allowed to possess or supply it and doing so can result in jail-time. This is a regulation under the Misuse of Drugs Act 1971, however cannabis is also regulated by The Misuse of Drugs Regulations 2001 which control the therapeutic use of drugs. Under this legislation, cannabis is regulated as a Schedule 1 drug which means it is not available for medical purposes and possession and supply are prohibited unless the Home Office approves.

cannabis plant seedlings

Cannabis: the sum of its parts

Cannabis refers to a group of plants which produce compounds called cannabinoids. Cannabis plants contain 113 different cannabinoids – so what exactly are we talking about when we talk about cannabis oil?

The two important cannabinoids to consider are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main part of cannabis that gives its psychoactive effects. It’s the compound that will make you feel ‘high’ if you smoke marijuana although this response is mediated by other cannabinoids too. It also stimulates release of the hunger hormone, ghrelin, which explains why people have an increased appetite when they take cannabis. It does this by binding to a specific receptor on the surface of cells in the brain.

CBD is non-psychotropic and it acts in a very different way to THC. But it might also enhance THC activity by increasing the number of receptors available for THC to bind to. It might also increase the levels of those natural endocannabinoids in the body.

In the UK, CBD is legal which means cannabis oils containing only CBD are legally available whereas THC is not legal.

four brown glass unlabelled bottles containing oil

Can cannabis treat disease?

In the UK, there are already two cannabinoid based treatments licensed for prescription. Nabilone is used to treat nausea and vomiting in people undergoing chemotherapy. There are other conditions it has been indicated for including IBS, fibromyalgia, chronic pain and parkinson’s disease however in the UK it is only permitted to help treat the side effects of chemotherapy.

The second cannabinoid based treatment available in the UK is Sativex which is used to treat the symptoms of multiple sclerosis including neuropathic pain and spasticity. Sativex is a cannabis extract which contains both THC and CBD.

Cannabis for epilepsy

When it comes to epilepsy – there is considerable evidence that THC can control convulsions through regulation of neuronal excitability and inflammation. But because it can make you high – it’s not an ideal avenue for therapeutic exploration.

Research into CBD for treating epilepsy is relatively new but initially promising at least for certain types of epilepsy and there is a drug awaiting FDA approval which can treat Lennox-Gastaut syndrome and Dravet syndrome, two severe forms of epilepsy. But this might not be sufficient in all cases – some patients may require different mixtures of THC and CBD to see an effect.

Cannabis for cancer

Cannabis can be useful in managing cancer-associated side effects in patients. It can act as both a pain reliever and a way to reduce nausea and enhance appetite. But there is early research that it might also kill cancer cells and stop them growing. In these cases researchers have looked at highly purified THC and CBD. Some trials have shown that combining chemotherapy with cannabis might have some promise. However, we have insufficient evidence to support its use as a cancer treatment either due to small study sizes or the research predominantly taking place in cells in the lab which is just not a good representation of what would happen in humans. We don’t know which types of cannabinoids are most useful, what doses are needed, what types of cancer respond, how to take them effectively and whether they should or shouldn’t be combined with other treatments.

Cannabis research

If cannabis is so promising, why don’t we do more research on it to bring it to clinical trial? Cannabis is a Schedule 1 regulated drug, it can only be used in research with Home Office approval. Schedule 1 drugs are so classified because they are not deemed to have medical usefulness. But researchers like Professor David Nutt are concerned that the medical usefulness of cannabis cannot be proven if research is prohibited.

Importantly, the recent media interest in cannabis use as a medical treatment has been useful in encouraging a UK government review on the therapeutic value of medications based on cannabis. This review will be undertaken by the Advisory Council for the Misuse of Drugs and may lead to a change in the legal status of cannabis and cannabinoids with regards to their use in medicine.

A woman standing at a laboratory bench facing away from the camera and wearing a lab coat

Alternative medicine

In the meantime, it is important to remember that while cannabis holds some promise as a potential therapy for many conditions, it is crucial to always follow professional medical advice when considering medical treatments. The research supporting cannabis use is limited and there are many questions about safety and efficacy that remain unanswered. For many conditions that cannabis might be useful for, we already have good medical treatments that can be used before considering an as-yet, unproven treatment. Cannabis oils are poorly regulated and might have wildly variable levels of cannabinoids and may even contain ingredients that are harmful. It is never advisable to buy medical treatments online or take medical advice from someone other than a qualified medical professional.

 

I talked more about this on my podcast, Skeptics with a K – on this episode. You can follow me on Twitter @AliceEmmaLouise for more.

Is sunscreen bad for you?

The weather has been glorious here in the UK, which means out come all the warnings to apply sunscreen copiously and frequently. It also means out come all the warnings that chemicals in sunscreen are dangerous.

But what does the science say?

Types of sunscreen

There are two main types of sunscreen: chemical or mineral. Chemical sunscreens contain chemical UV filters such as octinoxate and oxybenzone and some have retinyl palmitate added to them. Mineral sunscreens contain mineral compounds like titanium dioxide and/or zinc oxide. Chemical sunscreens absorb UV light and convert it whereas mineral sunscreens are reflective and act as a physical barrier. This means mineral sunscreens are often thicker and have a less pleasant texture on the skin and they leave your skin a little ghostly.

image of a person's knee with white sunscreen and a hearth drawn into the sunscreen

Chemical sunscreen – The warnings

When we see warnings about the dangers of sunscreen it tends to be related to three things:

  • Does chemical sunscreen cause skin problems such as contact dermatitis?
  • Does chemical sunscreen cause cancer?
  • Does chemical sunscreen cause birth defects?

So what are these concerns based on?

Contact dermatitis

Some people have skin reactions to chemical sunscreens – this occurs in less 1% of users and can be a response to fragrances, preservatives or the UV absorber itself. Sensitivity can develop after using a particular formulation for a long time. If you have a sensitive reaction to sunscreen you can try switching formulations, or you can switch to mineral sunscreen which is less likely to cause a reaction. And of course, see your doctor if you’re worried.

Causing cancer

Some studies suggest that oxybenzone can cause hormonal changes in cells grown in the lab. These hormonal changes have been confirmed in animals like mice but have not been reliably shown to occur in humans. Hormone changes can cause cancer so some people believe that oxybenzone can cause cancer. To date this has not been shown to be the case. Oxybenzone has not been shown to cause the DNA mutations needed to cause cancer and hormonal changes are not always linked to cancer. This evidence is insufficient to prove any link between oxybenzone and cancer.

an image of a small white mouse standing on a white background

Retinyl palmitate is sometimes found in sunscreen. Retinyl palmitate is derived from retinol or vitamin A and it acts as an antioxidant. Retinol generates reactive oxygen species (ROS) when exposed to UV radiation and ROS are able to damage DNA. This is the basis for the concerns that Retinol will cause cancer. Studies in mice did not show that retinol combined with UV radiation causes cancer. There is no data published in humans to suggest that retinyl palmitate causes cancer.

A recent meta-analysis confirmed that there is no evidence supporting an increase in cancer risk caused by sunscreen use.

Causing birth defects

There is evidence that medicinal retinol pills can cause birth defects however this has not been shown to be the case with topical retinol application. Still, as a precautionary method it is advisable that pregnant women do not use a sunscreen containing retinols for the duration of their pregnancy.

The context

It is important to note that while there may be some evidence suggesting some level of risk associated with chemical sunscreen risk – this must be taken within the wider context.

Skin cancer

There are two main types of skin cancer – melanoma and non-melanoma skin cancer. Non-melanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma and is largely treatable if it’s caught early. Non-melanoma cancers are the most common type of cancer. Melanoma skin cancer is an invasive form of cancer that is the 5th most common and at late stages is usually considered incurable. At early stages it is highly treatable but this form of cancer can progress rapidly and requires early intervention.  Both types of skin cancer are on the rise in the UK and this is linked to increasing sun and sunbed exposure. UV light exposure accounts for 86% of all melanoma cases, in the UK. Studies in Australia have shown a reduced rate of melanoma with regular sunscreen use.

A white sunhat with a black ribbon on a table with a pair of blue lensed sunglasses

Does sunscreen prevent cancer?

There is evidence that regular sunscreen use reduces pre-cancerous conditions and prevents skin cancer. However, the research into the efficacy of sunscreen is highly variable. This is partly because people are prone to using sunscreen in order to extend their time in the sun and misunderstand the most effective ways to use sunscreen. Chemical sunscreens should be applied to the skin 30 minutes before going into the sun and should be reapplied every two hours or more often if you are perspiring or swimming. Even waterproof sunscreen will be removed by towelling down after a swim. Sunscreen does prevent sunburn however research shows that people who only rely on sunscreen to protect themselves from UV damage burn more often than people who also practice sun avoidance habits. A person who has suffered sunburn more than twice in their life is twice as likely to get melanoma.

So what should you do?

While there is evidence that chemical sunscreens can have some detrimental effects on the body – the evidence is overwhelmingly clear that over-exposure to UV light causes skin cancer. Not only that, the research shows that the benefits of using sunscreen far outweigh the risks. Unless you are completely avoiding any UV light exposure then in my opinion, using sunscreen is a risk worth taking. In addition to wearing sunscreen and reapplying regularly, you should aim to avoid direct sunlight during the hottest hours of the day or wear clothing that covers your skin. And don’t forget, you might not burn through glass but you can still get UV skin damage through glass!

Extra reading:

https://www.skincancer.org/prevention/sun-protection/sunscreen/sunscreens-safe-and-effective

https://www.consumerreports.org/cro/sunscreens/buying-guide/index.htm

https://www.popsci.com/sunscreen-harmful#page-2

 

Kitchen cupboard “cures” – number one: turmeric

Wouldn’t it be great if we could cure all our ills with ingredients we can find in our kitchen cupboard? Plenty of people claim that it can be done and with the popularity of ‘natural’ medicines it’s not just your Nana who recommends it because that’s what her Nana taught her.

Kitchen cupboard remedies have become so mainstream that they become potentially dangerous when recommended for life-threatening diseases such as cancer. In fact, just a few months ago the Express asked “Can turmeric really cure cancer? Woman says benefits of golden spice ‘cured’ her disease”.

the express
Headline from the Express: “Can turmeric really cure cancer? Woman say benefits of golden spice ‘cured’ her disease”

But sometimes we wonder, if so many people believe it, maybe there’s really something in it?

In this series I will cover kitchen cupboard “cures” to investigate the claims made, and what the science really says. The series begins with the tasty Indian spice turmeric.

Turmeric

Turmeric is often reported as some sort of wonder spice. People who promote its use claim turmeric is anti-inflammatory, reduces cholesterol, treats diabetes, prevents Alzheimer’s disease and both prevents and cures cancer.

glass jar of orange coloured ground turmeric on a tea towel with a wooden spoon on the worktop next to it and turmeric on the spoon and counter

But actually, while this seems like a bizarre old wives’ tale, there is evidence supporting some of the claims for turmeric. The active ingredient in turmeric is curcumin or diferuloyl methane. Experiments in the lab show that curcumin alters the expression of genes in cells and some of these genes are related to specific pathways. For example, curcumin alters the expression of proteins related to inflammation in rat liver cells in a petri-dish and also alters the production of cholesterol in cells. Curcumin supplementation might also help manage some of the side effects of diabetes but only in conjunction with standard therapy. There is even some early evidence from mice with Alzheimer’s disease that curcumin can slow cognitive decline.

However, the science is also quite complicated. When it comes to cancer there is some evidence that curcumin can slow the growth of cancer cells in the lab but plenty of things slow cancer growth in the lab and never go on to prove useful therapies. Having said that, some clinical trials have shown that curcumin might one day prove useful as an adjunct to some cancer treatments in some cancer patients with some types of cancer.

The Express article above did discuss a case of a woman with myeloma, a type of blood cancer. This article was based on a single case published in British Medical Journal Reports in which a patient who had been on conventional treatment for many years suffered a relapse and was advised that there was nothing else doctors could do to help treat her cancer. The patient decided to take 8g chemical curcumin in tablet form per day in the hope it would treat her cancer. Her cancer has subsequently stabilised. This is a potentially interesting case – however it is only one single case that has been observed. Subsequent studies have not been done to investigate why this patient stabilised and there is insufficient evidence that it was the turmeric that was responsible. In fact, there are rare cases in which cancers such as myeloma can go into spontaneous remission without treatment and doctors believe this might be due to the patient’s own immune system targeting the cancer cells.

Important caveats

It would seem that the early research is fairly promising, however there are some very important caveats to remember here. So far, these studies are largely done in cells in a petri-dish or animals like mice or rats. We are not yet able to translate the findings to humans and we’re a long way from finding useful therapies using this compound.

Importantly, the studies use chemical curcumin rather than dietary turmeric and usually have specific measured doses. If curcumin becomes a useful therapy, the dose will change between different diseases and different patients. There is no evidence supporting the use of turmeric in isolation to treat disease. In all studies it is used as a supplement to standard therapy.

Clear capsules with orange powder inside

Medical treatments should always be managed by a medical professional. Any ‘herbal’ remedy has the risk of interacting with conventional drugs. In the case of curcumin research has shown that the chemical can inhibit some cancer treatments so it is important we understand the role curcumin plays in reacting with other medications before using this to treat patients.

It is because of this risk of interaction with other medications that it is really important patients taking any herbal remedy supplements speak to their doctors about whether these supplements might harm themselves or the efficacy of their treatments. It is important to note that many supplements are not fully regulated and therefore may contain ingredients that cause harm. For example, some curcumin supplements have been shown to contain anti-inflammatory drugs which can cause liver damage if taken in excess.

Summary: while there is some early evidence the active ingredient of turmeric might one day prove a useful supplement to conventional therapy we’re a long way from this being clinically useful. We need much more research to confirm the efficacy of curcumin and to establish which compounds work best and at which doses.

Next week I’ll be writing about Rosemary. If you have any specific requests for a Kitchen Cupboard “Cure” for me to cover, please leave a comment or send me a tweet @AliceEmmaLouise.

For more information on turmeric and cancer you can see CRUK’s review.

Sources:

 

 

 

Cool science: using Zika virus to treat cancer?

Throughout the last two years there has been a great deal of news on the Zika virus – a virus spread by mosquitoes which was first identified in 1947 in Uganda. In a normal healthy adult Zika fever causes relatively mild symptoms or even none at all however the 2015-2016 Zika epidemic gave rise to widespread concern due to its propensity to cause microcephaly and brain defects in babies infected with the virus during development. The epidemic was declared over in late 2016 although there are still travel warnings to certain areas where the mosquitoes known to carry the virus are prevalent.

But research into this particular virus highlighted an interesting trait that we might be able to take advantage of – Zika has a preference for stem cells.

Zika and stem cells

The reason Zika virus is particularly dangerous in developing babies is that the virus causes damage in stem cells in the brain. A stem cell is a cell that isn’t yet programmed. They’re really important in development because when you create a baby you start with one sperm cell, one egg cell and these cells needs to combine, proliferate and then differentiate into all the different types of cell within the human body. Stem cells are unique cells that can be programmed or ‘differentiated’ into all sorts of different types of cells. Once a stem cell has differentiated it can’t turn back into a stem cell – a differentiated cell is committed to only ever being that cell type. The adult body has very, very few undifferentiated cells but a developing foetus has plenty. This explains the risk of Zika infection during pregnancy as Zika has been shown to target neural progenitor cells – a type of undifferentiated cell in the brain – that might lead to the microcephaly seen in babies infected with the virus during their development.

480px-Zika-chain-colored
Crystal structure of the Zika virus

Zika and brain cancer

Cancer stem cells are quite a complicated thing that I’m not going to try and do justice in this post because it’s a topic that deserves its own post. Scientists believe that some cancers do have associated cancer stem cells. How exactly cancer stem cells might contribute to cancer progression is far from fully understood. However, we do believe that the presence of cancer stem cells might contribute to cancer therapy relapse. This is particularly concerning in glioblastoma – an aggressive form of brain cancer, which has poor survival rates despite our best efforts. Without treatment, median survival is around 3 months from diagnosis. With treatment we are able to extend that survival to 12-15 months however the cancer usually recurs. Scientists believe this recurrence is all down to the presence of cancer stem cells.

The study

So here’s the clever part. Cancer researchers know we have a problem in treating glioblastoma. They also realised that Zika virus is a relatively mild virus, which attacks stem cells. The adult brain doesn’t really have stem cells – unless the adult has glioblastoma. Cancer stem cells in the brain lead to cancer relapse; Zika attacks brain stem cells. Maybe we can make use of these two pieces of information.

So, scientists did some experiments. Firstly, they took some glioblastoma cells from patient tumours and they grew them in a dish in the lab. Then they infected them with Zika virus. They looked at either glioblastoma differentiated cells or glioblastoma stem cells. And they looked at the infection rate. Over 48 hours, over 60% of the stem cells were infected and this increased over time as the virus spread. The differentiated cells were infected too but not as much. What was especially interesting was that the stem cells infected with the virus had severely reduced ability to multiply and they had an increase in cell death. This was specific to only the stem cells and didn’t affect the differentiated cells. The virus kills cancer stem cells and prevents them from spreading.

Next the scientists took some patient tissue samples – this allowed them to look at a whole mixture of cells in a slightly more normal context without having to infect patients. They infected the tissue samples with Zika and saw that cancer samples were infected successfully and the virus only hit the stem cells and not the other cell types in the sample. They also looked at some brain samples from epilepsy patients and the virus didn’t infect them showing that the virus really is specific for stem cells!

jem.20171093
Glioblastoma tissue sample (from the paper)

 

Finally, they used the virus to treat mouse models of glioblastoma. They took mice with glioblastoma tumours in the brain and infected them with the virus. They saw that the tumours were much smaller and the mouse had improved survival when they were infected with the virus compared to control treated mice. They went on to show that they got an even better effect when combined with other glioblastoma treatments.

Benefits

Current treatments have two problems when it comes to glioblastoma. Firstly, the cancer stem cells make recurrence almost inevitable. This could drastically improve average survival times. Secondly, all brain cancer treatments have to be able to cross the blood-brain barrier in order to get through to the cancer cells. The blood brain barrier is an important way to keep things out of the brain where they might cause damage but it also serves as a way to keep brain tumours trapped in and harder to treat. Zika is great at crossing the blood-brain barrier.

What next?

We’re still such a long way from this being a useful patient treatment. In order to use this as a treatment we need to modify the virus in such a way that it will not spread from person to person and it will not cause the patient any harm. Currently virus work is always done in very specialised laboratories with expert training on how to prevent spread and with many, many precautions. If it were to be used as a therapy we’d need lots and lots of precautions to make sure it were safe. So far this has only been done in lab grown cells (albeit ones taken from patients mouse models of cancer. But it’s incredibly interesting research and a great example of how cancer research is so quick to develop and understand how we can take advantage of what we know about the disease and use that to treat it.

 

Please let me know in the comments if you’d like to see a post on any of the topics from this post – Zika virus, glioblastoma, stem cells?

If you found this interesting, please share it with three other people who might find it interesting too! Sharing cool cancer research gives us all a little more hope!

 

Image credit for the crystal structure of Zika: By Manuel Almagro Rivas – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048

Cool Science: taking advantage of cancer cell biology for cancer treatment

One of the big problems when it comes to treating cancer using drugs is that these drugs flood the patient’s body and cause detrimental side effects when they reach areas other than the malignant tumour.  Cancer cells are derived from our own healthy cells – they’re hard to target specifically without also hitting our healthy cells. A lot of research goes into trying to get around this problem. I came across a particularly interesting study that I thought I’d share here.

Earlier this year Sofie Snipstad et al. published a paper in Ultrasound in Medicine & Biology titled “Ultrasound improves the delivery and therapeutic effect of nanoparticle-stabilized microbubbles in breast cancer xenografts”. This paper was particularly cool because of the rationale behind it. Nanoparticle delivery of drugs is something scientists have been working on for a little while. The premise is that you take your drug and you wrap it up inside a small protective bubble allowing the drug to travel to a specific site before it is released. Due to a quirk of cancer biology, this is particularly great as a cancer therapy. When tumours grow, they start to form their very own blood supply – only the blood vessels that they grow are more leaky than normal blood vessels. They allow slightly larger molecules to pass through from the blood vessel and into the surrounding tumour.  This means we can use nanoparticles to deliver cancer drugs specifically into tumour sites by allowing the particles to travel through these leaky blood vessels. But then we hit another problem – if the tumour blood supply doesn’t reach the very depths of the tumour then the particles are too big to get all the way through. You can treat the edges but not the very centre of the tumour. So, this paper worked on a special combination – they took a bunch of nanoparticles containing chemotherapy and they bundled them up together into microbubbles that can travel around the blood system easily and safely until they reach the tumour site. Then, the researchers used a focused shot of ultrasound to break up the bubbles and release the nanoparticles. This also served to allow gentle tissue massage by the ultrasound to allow the nanoparticles to distribute further throughout the tumour. Once in the tumour, the cancer cells start to take up the nanoparticles and inside the cell the drug is released and can kill the cancer cell from the inside.

Picture1Image: figure from the paper

Any microbubbles that weren’t in the tumour site and therefore not exposed to the focused ultrasound could be easily cleared from the body without releasing the drug which means the only cells targeted by the therapy are the cancer cells. This means we can hit the cancer cells with a higher, more toxic dose because the healthy cells are not going to be hit with the same dose.

The researchers in this paper were testing the optimal way of doing this in mice suffering with triple negative breast cancer – one of the more aggressive forms of the disease – with positive results. The mouse tumours took up the drug 2.3x better and there was no tissue damage identified. All of the tumours either regressed or else the mice went into complete remission. The authors described this as a “promising proof-of-concept study”.

New Study: Does chemotherapy promote cancer metastasis?

A little while ago my attention was drawn to an article published in July 2017 on a blog called The Mind Unleashed titled “Chemotherapy to Spread Cancer, Cause Lethal Tumours in Groundbreaking New Study”. The article reported on a paper published the same month in the journal of Science Translational Medicine. This article claimed that the researchers had “proven that chemotherapy causes cancer cells to spread throughout the body – to replicate themselves, making your cancer worse, not better”.

This is a frightening thought. Could it be possible that in treating cancer we are actually promoting its survival? As a cancer researcher I was very, very sceptical of this claim. Chemotherapy is a cancer treatment that has been available for a long time. It was first studied in the early 20th century and first administered in 1942. On the day of writing there are over 2.9 million papers referencing the term chemotherapy in the title, key words or abstract available on PubMed (a database for published, peer-reviewed material). We have done an incredible amount of research into different types of chemotherapy treatments and those that work are the only ones approved for use in the clinic.

That’s not to say we know everything about chemotherapy, though. The human body is a complicated thing, as is cancer. We might well be missing something. The most important part of research is to continually progress, to follow the science where it leads us in the most unbiased way possible.

*

The paper in question is one reporting a study undertaken by researchers at Albert Einstein College of Medicine in the US. The authors were working on a particular chemotherapeutic agent called paclitaxel (brand name Taxol) in mouse models of breast cancer.

Paclitaxel is a drug derived, originally, from the bark of the Pacific Yew tree. It was first discovered by a screen on plant derivatives undertaken by the National Cancer Institute in the early 1960’s. After decades of research into the chemical – first isolating the chemical structure and later the mechanism of action – paclitaxel was approved by the FDA in 1992. Today, we make it from a precursor taken from the needles of this plant. We are unable to produce it entirely synthetically.

Paclitaxel works – it prolongs progression free survival and shrinks tumours. The mechanism of action is well established; paclitaxel binds to a protein involved in cell division thus preventing tumour cell replication. Consequently those cancer cells die and tumour size is reduced.

cancer cells, cell division, cancer research

There are, of course, side effects to any drug and paclitaxel does have a number of them. In particular, paclitaxel is not soluble in water so for treatment it must be diluted in a derivative of castor oil. This is not particularly well tolerated by the human body and patients must be co-treated with corticoids and antihistamines to prevent dangerous hypersensitivity reactions so research is ongoing into better ways of administering paclitaxel.

One avenue of research has been into a particular quirk of paclitaxel treatment. It has been identified by clinical trial that when paclitaxel is used prior to primary treatment (such as surgery) in breast cancer (known as a neoadjuvent therapy) the survival rate of patients is not increased beyond that of surgery alone. This is despite a reduction in tumour size when using paclitaxel as a neoadjuvent. If tumour size is reduced you might expect survival to be enhanced – there was a discrepancy here not currently explained by the available science.

The authors of this paper had a theory. They knew that paclitaxel treatment is associated with an increase in a particular type of immune cell called macrophages moving into the tumour site. They also knew that macrophages might be involved in metastasis. Therefore, they posited that perhaps the reason paclitaxel didn’t prolong survival despite shrinking the tumour might be because the tumour was able to sustain itself by travelling elsewhere in the body.

They investigated this question in a number of laboratory mice which suffer from breast cancer and are used as models of the disease in humans. The researchers found that there was an increase in markers for metastasis in those breast cancer mice treated with paclitaxel and an increase in circulating cancer cells in the bloodstream. And then they took it another step forward. The authors noticed that the increase in metastasis markers included an increase in a protein called TIE2. They had reason to believe that this was an important part of the problem so they co-treated the mice with an inhibitor against TIE2. This they showed reduced the markers of metastasis and the circulating cancer cells in the blood.

mouse model, science, laboratory, cancer research

The important conclusion of this study was not that paclitaxel might promote metastasis in mice with breast cancer. It was that this particular type of chemotherapy might have another negative effect we didn’t know about. It is important to know about this because now we can monitor patients for changes in their metastasis markers when they are treated with this type of chemotherapy and we can switch them on to a different form of treatment if necessary – or we can co-treat them with TIE2 inhibitors. The most important thing in medicine is to have as much knowledge as we possibly can. We shouldn’t be fearful of negative effects of good treatments – unfortunately to kill cancer cells in the body will have some negative effects. But we need to be aware of them and we need to manage them carefully and make sure we put the needs of patients first. Research like this helps us make informed decisions on treatment options. Of course it requires further research first in more animal models and later in humans but it a stepping stone to giving us important information that may well help us to save more lives.

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What worries me more is that blogs like The Unleashed Mind misrepresent the data reported and promote distrust in reliable medical research and the scientific method in general. Anyone communicating the findings of academic research has a responsibility to represent it accurately especially when that communication might well influence a patient’s decision when it comes to their health. A cornerstone of medicine is to give patients the opportunity to informed consent – we should all endeavour to present the information as accurately as is possible.

photo credit: ZEISS Microscopy