Leiden scientists tackle cancer at the source

Cancer is now the number one killer in the Netherlands. Each year World Cancer Day (4 February) is a time to reflect upon the consequences of this disease and the best way to fight it. Bioscientists from Leiden are studying cancer at the most fundamental level, which puts them at the source of new treatments. This is just some of their current, groundbreaking research.

Fighting tumours with light

Only a fraction of chemotherapy regimens actually reach the tumour. What is more, chemotherapy is not selective: it also kills healthy cells and consequently causes serious side effects. Chemist Sylvestre Bonnet wants to combine chemotherapy with light, to create a less harmful cancer cure.

What is he researching?
Bonnet is developing anti-cancer molecules that are activated by light. The molecules contain the metal ruthenium. This metal binds to molecules and has photochemical properties, which means light can cause the ruthenium complex to change.

What has he discovered?
Bonnet has come up with a way of switching off the toxicity of ruthenium in the body. He modifies ruthenium complexes with biotin and methiotine, and this prevents the ruthenium ion from binding to other molecules on its way to the tumour. The tumour is irradiated with light in order to activate the new molecule locally and cause it to destroy the cancer cells. The rest of the body is spared, because the fraction of the chemotherapy dose that does not reach the tumour remains inactive.

What does this mean in terms of further research/treatment methods?
Bonnet has patented the idea, and he wants to work with medical institutes and private partners in the future to ensure that these new molecules do actually reach the patient. For patients it will mean that they must not be exposed to too much light during the treatment, to avoid activating the medication prematurely. Furthermore, the focus is to ensure that as much as possible of the administered medication ends up in the tumour rather than elsewhere in the body. Bonnet says, ‘That is what we, like many other researchers, are trying to achieve with the aid of nanotechnology.’

Bonnet’s molecules have to be irradiated with light to become toxic

Bonnet’s molecules have to be irradiated with light to become toxic

Fine-tuning cancer treatment by separating waste in the cell

Hermen Overkleeft is Professor of Bio-Organic Synthesis, which means he makes new molecules. Overkleeft works on the proteasome, one of the most important degradation mechanisms in the body. This large protein complex in the cell degrades unnecessary or damaged proteins.

What are you studying?
‘There’s a medication, Bortezomib, that functions as a proteasome inhibitor. It’s used as a last resort big-gun treatment for aggressive cancers of the blood such as Kahler’s Disease. The idea behind it is that a tumour cell has a higher protein dynamic than a healthy cell. It’s a complete miracle that we can partially disable something as widespread and ubiquitous as the proteasome. What I do is look in minute detail at what happens in that proteasome, so that we can fine-tune the medication. The tumour cell gives up the ghost but the healthy cell does not. We also hope to be able to use the treatment for solid tumours.’

What have you discovered?
‘The proteasome cuts proteins into three different residues: fatty, acid and alkaline. We have studied all combinations of enzyme activity, and therefore know which enzyme inhibitor is best at destroying the tumour cell and which one doesn’t work at all. Disabling the acid and alkaline activity together, for example, has no effect. Disabling the fatty and alkaline activity together works best.’

What does this mean in terms of further research/treatment methods?
‘It means that we’re going to focus on the latter combination, in the hope of finding the optimal regime are being able to combine both activities in a single complex. I have applied for a patent together with a Swiss haematologist and a proteasome physiologist from America; we hope that the pharmaceutical industry will do something with it. But I first want to take a step in the direction of the patient to find out whether the complex is toxic and whether it is absorbed well in the body. Our new tenure tracker Mario van der Stelt is going to do this.’

Spread of cancer slowed by switching off genes

Bob van de Water, Professor of Drug Safety Sciences, is reconstructing the way in which breast cancer spreads. His research teams works closely with the Erasmus MC.

What are you studying?
‘We are trying to find out how breast cancer spreads and which genes play a part here. We are doing this by following the migration of human breast-tumour cell cultures and switching off genes one by one to see what effect that has on the migration. This is generating new options for developing medication.’

What have you discovered?
‘We have found a number of genes that play a part in the spread of breast cancer, such as the SRPH1 gene. Our research with the Erasmus MC has shown that the cancer is more likely to spread if this gene is more active. And in animal models the spread of breast-cancer cells is inhibited if we switch off this gene.’

What does this mean in terms of further research/treatment methods?
‘It isn’t yet possible to switch off SRPH1 in humans. We first need to find out whether this has adverse effects upon other vital organ systems in the body. We also still need to understand how SRPK1 interacts with other gene products in tumour cells. These latter genes may actually prove easier to influence than SRPK1. It is to be hoped that new research will prove this.’

How tumours develop and spread: normal tissue (1), primary (epithelial) tumour with low expression of Annexin A1 (2) basal cell tumour with invasive behaviour (the arrow indicates the increased expression of Annexin A1) (3) secondary tumour elsewhere in the body (4).

How tumours develop and spread: normal tissue (1), primary (epithelial) tumour with low expression of Annexin A1 (2) basal cell tumour with invasive behaviour (the arrow indicates the increased expression of Annexin A1) (3) secondary tumour elsewhere in the body (4).

Driving cancer cells to suicide

Cell biologist Erik Danen from the Leiden Academic Centre for Drug Research (LACDR) is studying how cells ‘commit suicide’ once their DNA has become irretrievably damaged. This is helping to answer the question of how cancer cells can defy the human defence mechanism and chemotherapy.

What are you studying?
‘Cells have the ability to recognise and repair damaged DNA. If the damage is too great, cells are given the order to die away. But cancer cells often stay alive, even with damaged DNA. We have documented the network of signals that control this suicide process. We looked at which genes are involved and which changes take place in proteins.’

What have you discovered?
‘We have discovered a mixture of positive and negative signals that together ensure that cells can determine exactly when the DNA damage is too great to repair and that they must consequently commit suicide. If some genes that play a part in these signals are switched off, it can mean that damaged cells commit suicide much faster.’

What does this mean in terms of further research/treatment methods?
‘We are now looking into which of the genes that we found can increase sensitivity to irradiation or chemotherapy if they are switched off. The next step will be to look at whether the enzyme that this gene makes can be inhibited with a chemical substance. This is the starting point for the development of a medication that reverses the insensitivity of cancer cells to treatment.’

Accumulation of active protein p53 (left) and activation of the p53 signal network as a response to DNA damage.

Accumulation of active protein p53 (left) and activation of the p53 signal network as a response to DNA damage.

Zebrafish embryos reveal the route cancer cells take

Leiden biologist Ewa Snaar-Jagalska uses the embryos of transparent zebrafish to see how cancer cells spread. Her discovery could have a major impact on the clinical treatment of cancer.

What is she studying?
Ewa Snaar-Jagalska and her fellow biologists at Leiden University’s Cell Observatory are studying the route that cancer cells take. They are using zebrafish embryos for this because they are transparent, which makes it easy to follow the spread of tumours.

What has she discovered?
The research team has discovered that specific white blood cells – neutrophils – have a crucial role. Neutrophils are immune cells that were always thought to have an inhibiting effect on tumours. They do inhibit the growth of primary tumours, but the transparent baby zebrafish have also shown that neutrophils pass straight through all sorts of tissue, and that the breakaway cancer cells follow their precise route.

What does this mean in terms of further research/treatment methods?
This discovery could have a major impact on the clinical treatment of cancer, says Snaar-Jagalska. Patients often take what are known as angiogenesis inhibitors that inhibit the growth of primary tumours; a side effect, however, is that these inhibitors can cause additional secondary tumours. It may be that this medication stimulates the migration of neutrophils. The researchers are using this knowledge to try to influence the process. For example, they can switch off genes one by one to see what the consequences, and test potential new medications that prevent secondary tumours on zebrafish embryos.

Ewa Snaar-Jagalska uses zebrafish embryos because they are transparent, which makes it easy to observe the spread of tumours.

Ewa Snaar-Jagalska uses zebrafish embryos because they are transparent, which makes it easy to observe the spread of tumours.

New vaccination to fight cervical cancer

Ferry Ossendorp is Professor of Molecularly Defined Vaccine Biology at the LUMC. He works closely with colleagues from the Faculties of Medicine and Science. This makes it possible to design good synthetic vaccinations.

What are you studying?
‘As a tumour immunologist I develop new vaccinations that activate the human immune system to attack cancer cells. Some types of cancer, such as cervical cancer, are often caused by a virus. We are researching how we can mobilise immune cells so that together they dispose of the tumour. It is therefore not a preventative vaccination but a therapeutic vaccination for women who already have cancer. A significant advantage is that it has far fewer side effects than chemotherapy and irradiation.’

What have you discovered?
‘We now know the best way to make synthetic vaccinations, and that we can generate a very effective defence against cancer cells if we combine these peptides with an immunostimulator.’

What does this mean in terms of further research/treatment methods?
‘The new vaccination will be tested on patients for the first time this year. If it works well, it will still take five to ten years before the vaccination actually comes on the market, if at all. There is growing appreciation that more types of cancer are related to a virus, and this means that therapeutic vaccinations may be possible for other types of cancer.’

Pimping the immune system

Chemical biologist Sander van Kasteren is developing chemical substances that help the immune system do its work better.

What are you studying?
‘I’m looking for new ways to pimp the immune system. Antigen-presenting cells sample their surroundings to check for the presence of bad cells. If that is the case they cut a bad cell, such as a cancer cell, into pieces. They present these pieces to T cells, the soldier cells of the immune system, which then launch the attack. But antigen-presenting cells are often too enthusiastic in cutting up the bad cells, which makes the pieces too small for T cells to recognise them. I make substances that alter the speed of this cutting process, and this allows anti-cancer vaccinations to work more efficiently.’

What have you discovered?
‘It has proven possible to influence this cutting process positively. In a first test with a vaccination model we achieved a fourteen-fold increase in the immune response.’

What does this mean in terms of further research/treatment methods?
‘We are now taking the step towards applying these substances to real anti-cancer vaccinations. We are focusing here on those cancers, such as cervical cancer, that are caused by a virus but also on cancers, such as colon cancer and skin cancer, that are not caused by a virus. If we can translate the results with the vaccination model into a real anti-cancer vaccination, it will have a huge effect on the future immunotherapy against this disease.’


(29 January 2013 – LvP/HP)

See also

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Last Modified: 11-02-2013