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The Witney Group at UCL's Centre for Advanced Biomedical Imaging. Specialising in the development of advanced cancer imaging tools.


Flexibility is a killer

Tim Witney

I'm often asked why, despite many $/£ millions have been spent on cancer research, it seems like we're no closer to a cure. This is quite a difficult question to answer, because there are a number of factors that contribute to cancer being such a tough disease to treat. I should point out though, that some really great progress has been made in recent years, exemplified by breakthrough immunotherapy drugs, where our own immune system is trained to kill the cancer; or new combination drugs that target specific genetic mutations found in many cancers. Also, as Cancer Research UK's very informative website states, cancer survival rates have doubled in the last 40 years. But this really isn't good enough. There are a variety of reasons why we're struggling to do better, but in my mind there are two predominant reasons why cancer is such a moving target:

1. Each cancer is different and specific to each individual patient. Cancer results from problems arising in our own DNA, known as gene mutations. The problem is that for each person, these 'problems', or mutations, occur in different places in the DNA, affecting different genes. Each mutation really needs a different treatment, meaning that we need a whole library of drugs to be effective. There are efforts to try and tailor each treatment to individual patients, known as personalised, or precision medicine

2. Cancers are adaptable. By their very nature, they are designed to grow and outcompete normal healthy tissue that surround them. They co-opt new blood vessels to provide them with the nutrients they need, and can change their behaviour in order to survive, say drug treatment, or to enable them to grow in harsh environments. 

Over the past couple of years at Stanford University, I've worked on trying to better understand how this adaptability gives cancer an unhealthy advantage over normal cells, and the organs they colonise and take over. One element of flexibility that cancer cells possess is the ability to choose how they use the sugar they take up. Sugar, in the form of glucose, is needed for all cells in order to create energy that keeps the cell alive. To produce this energy, glucose is taken up by cells and converted to other molecules in a process called 'glycolysis'. When oxygen is present (the reason why we need to keep breathing!), these molecules are further modified and energy is produced. Cancer cells have generated a unique ability to put the brakes on this process. On the face of it, this seems like a bad idea, but what this means is that the molecules of glycolysis usually used for creating energy can now be used to make other things, such as new bits of cells. The result is that more cancer cells are produced. Cancer cells can quickly switch between these two states: 1) energy production; or 2) the creation of new building blocks to create more cancer cells. 

  Fig. 1. PKM2 controls the balance between the production of new building blocks or energy in cancer cells. Here, PKM2 is represented by an orange sphere.  


Fig. 1. PKM2 controls the balance between the production of new building blocks or energy in cancer cells. Here, PKM2 is represented by an orange sphere.  

We're now starting to understand what controls this flexibility inside cancer cells, and it's an enzyme called pyruvate kinase M2, or PKM2. PKM2 has been found in all cancer cells studied to-date, and acts as the master regulator of glycolysis. When the cancer cell requires energy, PKM2 binds to 3 other identical PKM2 enzymes, but when new building blocks are needed for the creation of new cells, PKM2 only binds to one other PKM2 enzyme, blocking energy production almost completely (Fig. 1). Most normal healthy cells lack PKM2, instead using an enzyme, PKM1, that always leads to energy production.

Fig. 2. DASA-23 binding to a tumour in the brain of a mouse, indicated by the arrow.

Fig. 2. DASA-23 binding to a tumour in the brain of a mouse, indicated by the arrow.

In the lab of Sanjiv Sam Gambhir at Stanford, my colleagues and I worked on ways to try and detect this cancer-related enzyme in animal models of human brain cancer. We reasoned that if we could detect PKM2, we may be able to detect the cancer itself. This would be massively helpful to the brain surgeon when they came to remove the brain tumour as they would know its precise location within the brain. This is important, as the surgeon doesn't want to take too much healthy tissue, which may result in unwanted side effects, or be too cautious and leave some of the tumour behind. We developed a new positron emission tomography imaging agent (see earlier posts for an overview of this technique) based on a known drug, DASA-23, that specifically targets PKM2. By tagging DASA-23 with radioactivity and injecting it into mice, we could see its precise location within the animal and how that changed over time. As shown in Fig. 2, the tagged DASA-23 honed precisely to the PKM2-containing brain tumours and not to the healthy surrounding brain tissue. Moreover, we showed that by adding another drug that targeted PKM2 we could stop DASA-23 binding to the tumour cells. This showed that the new drug was going to the right place, meaning that DASA-23 might be useful for the development of new PKM2-specific drugs. Although exciting, it should be pointed out that these are very early findings and a lot more research is needed before we will be able to use DASA-23 in hospitals around the country, but early tests in humans are planned for next year.

If you're interested, this work was published as the front cover of this week's Science Translational Medicine