Category: science

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.

*

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