Where’s that Tumour?

It’s handy that in the last piece we summarised the Grand Plan of President Obama’s Moonshot and the UK’s complementary Grand Challenges for cancer because it’s a good backdrop to some results presented a month ago at the European Breast Cancer Conference in Amsterdam. As ever, the newspapers reported them under ‘staggering’ headlines – but this time you couldn’t really blame them as one of the boffins involved, Nigel Bundred of Manchester University, described the results as mind-boggling.’

Prepare to be boggled

What was reported was a small-scale trial (257 women) of a treatment for one of the most aggressive forms of breast cancer – HER2 positive. This subtype of breast cancer takes its name from a protein that spans the cell membrane and can pass a signal from outside to in. That makes HER2 a ‘receptor’ – you can think of receptors as two blobs of protein joined by a wiggly bit that sits across the cell membrane. When something sticks to the outer bit the receptor changes shape to accommodate it. It’s rather like shaking hands with someone: the shape of your hand changes as you grip theirs. The clever bit is that a relatively small change in the blob on the outside of the cell is transmitted to the blob on the inside via the trans-membrane bridge (or wiggly bit).

HER2 is unusual: rather than having its own messenger floating around in the circulation, it gets switched on by sticking to another cell surface receptor – such receptors are rather touchingly called ‘orphans’. HER2 is a bit of an incestuous orphan, being particularly fond of HER3, a close relative – and when these two are drawn into an embrace on the outside of the cell their internal blobs have to follow suit – it’s difficult to kiss while keeping your bottom halves far apart. This drawing together of the internal blobs in turn causes them to change shape – not a lot but just enough to act as a signal. For HER2 that signal is an enzyme activity: it gets turned on as a kinase – so it adds phosphate groups, specifically to tyrosine amino acids, in target proteins. It’s a receptor tyrosine kinase. Switching it on activates downstream pathways that signal to the nucleus, telling the cell to go forth and multiply.

Because there are lots of signal pathways in cells that send messages in straight lines but can also ‘cross-talk’, it’s a bit like a blancmange: poke it in one place with a chemical (messenger or drug) and the whole thing wobbles.

Fig. 1. 114

The cell as a blancmange. Receptor proteins span the outer membrane and most pass a signal from outside to in as a response to the arrival of a chemical messenger. HER2 is unusual because it works by linking with other receptors (e.g. HER3): the intracellular pathways thus activated include RAS-MAPK.

Healthy breast cells have about 20,000 HER2 proteins but tumour cells may have 100 times more – i.e. 2 million receptors. So it’s easy to see that if you jack up the number of signallers by 100-fold you’re likely to have a pretty hefty proliferation push. The cells just keep on making more and more of themselves in an uncontrolled way – that’s cancer.

One of the main downstream signalling pathways from HER2 is RAS-MAPK that we’ve met before as a seductive target for blocking by anti-cancer drugs.

But, because multiple pathways can be switched on, hitting a single target often doesn’t work too well.

What’s new?

The usual treatment for breast cancer is primary tumour removal by surgery followed by a combination of radiotherapy and drugs. One of the most successful drugs for treating cancers with high levels of HER2 has been trastuzumab (brandname Herceptin). Herceptin is an antibody that sticks to HER2, prevents the receptor interacting with other proteins (including HER3) and thus blocks uncontrolled signalling.

The study that’s just been reported had two novel twists. The first was to try Herceptin before surgery. The second was to combine Herceptin with another drug – one that hits the enzyme activity that turns on the signal pathways inside cells.

A big turn-off: kinase inhibitors

Lapatinib (Tykerb/Tyverb) is a small molecule that inhibits the tyrosine kinase activity of HER2. It’s been used hitherto where a cancer has progressed after treatment with other drugs. About a dozen kinase inhibitors currently have Food and Drug Administration approval with many more in clinical trials. Perhaps the best known is imatinib (Gleevec), used for the treatment of chronic myelogenous leukemia.

Combining Tykerb with Herceptin hits the signal pathway two different spots. The idea is to give the tumour cell two problems to overcome in the hope that it will fail. It’s a strategy that has met with some success in other settings – meaning that some patients have had extended survival times.

In this study 66 women were given the combination therapy and the results clearly came as a serious shock to one and all. In almost nine out of ten cases there was an immediate response but in 11% tumours entirely vanished over a two-week treatment period. That is truly astonishing. Even in the most successful mouse experiments it is a very rare event for tumours to disappear. In a further 17% of the women tumours shrunk to less than 5mm – a growth so small it is classed as “minimal residual disease”.

Fig. 2. 114

Poking the blancmange. Two shots at blocking signalling in a cancer cell with high levels of the HER2 receptor. Herceptin prevents HER2 interacting with other proteins, especially HER3, whilst Tykerb blocks any residual tyrosine kinase activity.

 A big question, of course, is why complete responses only occurred in one in ten cases – and it underlines the need to know more about what makes a tumour, as we noted last time. That aside, one very encouraging aspect is the short treatment period required for a response. Tyverb was turned down by NHS rationing bodies for not being cost-effective at £27,000 a year – much the same as Herceptin. However, the combined therapy would be about £1,500 per patient. Assuming that the complete responders really are in long-term remission, that would represent a financial transformation almost as astonishing as the biological result.

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A Radiant Visitor

In an historic first, Cancer For All welcomes a guest, Stacey McGowan, who is a physicist just starting a Ph.D. on something called Proton Therapy. She is a member of the Department of Oncology in Cambridge and you can find out more about her in her blog www.planningforprotons.com but today she is going to take us into her world with a simple guide to radiotherapy in the treatment of cancer.

As undergraduate there was a lot of pressure to know what you wanted to do after graduation. I knew I wanted to stay in physics as it was what I loved; I also knew I wanted a job that meant something to me. I did not want to work in finance or for a defence company. At the time I also didn’t think I wanted to go into research! This seemed to have left me with two options, to work in the energy industry, or in medicine.

A lot of people, including my undergrad self, are unaware of medical physicists and their role in the hospital and in treating patients. After an inspiring talk at a careers event from a medical physicist working in the NHS I knew that this was what I wanted to do after graduation: I wanted to be a medical physicist.

There are three main methods for treating cancer; surgery, chemotherapy and radiotherapy. A patient will usually receive one or more of these methods as part of their treatment. Of the cures achieved about 49% of them involve surgery, 11% involve chemotherapy and 40% involve radiotherapy. However of the NHS’s cancer budget surgery costs around 22%, chemotherapy 18% and radiotherapy just 5%. This makes radiotherapy both a successful treatment option, sometimes on its own but usually in combination with surgery or chemotherapy, and it is extremely cost effective. Despite this many people don’t really know what radiotherapy is and the prospect of it as a treatment often makes patients apprehensive. As much as radiation sounds scary, we are exposed to it all the time in nature from the sun and soil and nowadays in our homes from electrical devices including Wi-Fi and mobile phones. In addition, we use it in many diagnostic applications including X-rays, CT scanners and nuclear medicine.

The difference between the radiation used for cancer treatment and that received from other sources is in the amount of radiation, or dose, delivered. When I talk about dose, think of it in the same way you would any other type of medicine. An oncology doctor will prescribe a course of radiotherapy with a specific dose to be delivered to the patient every weekday for between 4 and 6 weeks. The radiation is delivered in the form of X-rays – highly energetic particles of light – delivered at higher energies and doses than those used to image a broken bone (Editor’s enlightenment: physicists tend to use the word ‘light’ to mean electromagnetic radiation of any wavelength – not just what the eye sees). To create such highly energetic light we need a powerful machine that can also precisely deliver the X-rays to the part of the patient where the cancer lies. This machine is known to the medical community as a linac, and to the scientific community as a linear accelerator!

The linacs used in the hospital differ from those used in physics research as medical linacs have a very different role and it is the medical physicists’ job to ensure they work as intended. The X-rays delivered to the patient will harm cells in their body, both cancerous and healthy, by damaging their DNA. It is extremely important that the cancer cells receive the dose necessary to kill them so that they cannot continue to grow, resulting in a cure. It is also a priority that healthy tissue receives the smallest possible radiation dose to ensure a low chance of long term side effects. To accomplish these goals linacs are designed to rotate about the patient so that the tumour can be targeted from more than one direction. Treatment is usually delivered in daily doses (known as fractions) over a period of a few weeks because healthy cells are better at repairing damage to their DNA than cancer cells, so they can recover from each dose, whereas damage will accumulate in the tumour cells. Cumulative DNA damage leads to cell death, stopping the cancer in its tracks.

Linacs can also shape the beam so that it will match the shape of the tumour, shielding the adjacent healthy tissue from the highest radiation doses. To produce such patient-specific and intricate treatments powerful computer programs are used to design the treatment based on images of the patient (usually CT scans). Oncologists and physicists will work together, distinguishing cancer tissue from healthy, choosing beam directions and designing beam shapes to ensure that the patient receives the optimal treatment.

Many types of cancers respond to radiotherapy including those of the lung, breast, prostate, brain and spine and the method can be used to treat both adults and children. The short term side effects from radiotherapy vary depending on the region being treated. For example, radiation of the abdominal area may cause digestive and bowel discomfort or if the head and neck is the target, the patient may experience difficulty swallowing and develop a dry mouth. Generally radiotherapy can lead to tiredness, nausea and skin irritation in the targeted areas. Long term side effects can include secondary cancer, more probably in young patients, and growth problems in children.

The future of radiotherapy in the NHS is to use of protons and not X-rays to deliver radiation for specific types of cancer. The nature of protons makes the aim of cure without complication more achievable and is the topic of my PhD research.

Unlike X-rays, protons have a finite range (we can choose where they stop) which reduces the amount of radiation exposure to the patient, making this form of therapy especially beneficial for spine and brain tumours in adults and for most cancers in children. Proton therapy is particularly attractive for treating childhood cancers because it is less likely than conventional radiotherapy to cause growth defects and other health complications, including the development of cancers in later life.

Despite the UK lacking the facilities necessary to treat cancer using proton radiotherapy, a limited number of NHS patients are currently offered this option abroad as part of the NHS Proton Overseas Programme. The Government also announced in April 2012 that two proton centres will be established in England, in Manchester and in London. It is hoped that these will start to treat patients by early 2017.

Stacey McGowan

Department of Oncology, University of Cambridge

http://www.planningforprotons.com