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Cancer pathogenesis and therapy

Research

Combining different disciplines, Leiden University researchers work together to formulate innovative solutions to societal problems. Below is an example from the field of health and wellbeing.

Overview research dossiers

Fighting cancer efficient with an eye towards quality of life

With  cancer, a person’s body cells grow uncontrollably. Putting together a detailed picture of how this comes about makes it possible to develop efficient therapies. Researchers at the Leiden University Medical Centre (LUMC) and Leiden University are working together to gain a better understanding of different forms of cancer and to develop new, more efficient medications and treatments that both cure patients and give them a good quality of life.

An illness that is hard to stop
A healthy cell divides only when it is necessary for either growth or repair. In contrast, cancer cells multiply much more frequently and have escaped the natural control mechanisms. Changes in genetic material, known as mutations, are at the root of unbridled cell division. A cancer cell develops in steps, through an accumulation of mutations in genes involved in cell division. The immune system usually disposes of cells with harmful mutations, but when it doesn’t recognise cancerous cells or is unsuccessful in killing them, these cells can grow into a tumour.


Quality of life
It is becoming increasingly clear that cancer is a complex disease that develops differently in each patient. Molecular and genetic research provides researchers with more insight into how tumours are formed, and this knowledge allows us to develop new medications and treatments.
It’s not only tumours that differ from each other; the same is also true of patients. One patient may be quite young, while another is advanced in age. That calls for a personal approach to ensure the best possible quality of life at each stage of life.
Not only are new therapies being worked on; existing treatments are also constantly being improved. For example, Leiden researchers are working to reduce the side effects of chemotherapy, and LUMC surgeons are making increased use of fluorescent light in their operations to render a tumour more visible, allowing its removal with greater precision.


Precision medicine and stimulating the immune system
Over the last few years, an increasing number of medications have been appearing that target specific traits of cancer cells. For instance, there are now medicines that specifically inhibit the molecules responsible for uncontrolled cell growth. In Leiden, our researchers are developing and testing new substances for development into cancer drugs. A great deal of effort is also being put into immune therapy, in which the patient’s own immune system is stimulated to vigorously fight cancer cells. In Leiden we have had successes treating gynaecological tumours with a form of immune therapy that is still in an experimental stage.


Multiple strategies
What makes treating cancer so difficult is that a tumour often finds ways to escape the therapy and continue growing. Multiple strategies and combination therapies are needed to outwit such clever tumour cells, along with working together with different types of researchers to find an optimal treatment. This allows doctors to provide patients with better treatment with fewer side effects.

The LUMC is the linchpin for cancer research in Leiden. LUMC medical specialists work together with Leiden University chemists and biologists, as well as with other researchers both in this country and abroad. One unique advantage in Leiden is the Bio Science Park, which is home to a number of innovative businesses, as well as to the Leiden Academic Centre for Drug Research (LACDR), the Leiden Institute for Chemistry (LIC) and the Centre for Human Drug Research (CHDR). These bodies constitute an indispensable link in the chain of patient care.

Multidisciplinary research is also carried out beyond the borders of Leiden; for example with TU Delft and Erasmus University Rotterdam in the Particle Therapy Centre Holland (PTC).


Cancer pathogenesis and therapy research at LUMC
O
ncology Centre LUMC
Holland PTC

 

Cancer cells: A closer look

What distinguishes a tumour cell from a healthy cell? Researchers are trying to answer this question as precisely as possible. Certain differences could eventually lead to new therapies.


Understanding tumours
‘We are looking very closely at differences between tumour cells and healthy cells,’ explains Peter ten Dijke, professor of Cellular Biology at LUMC. Tumour cells often contain active substances other than those found in healthy cells. In other cases there is either more or less of a particular molecule than is normal. ‘When we understand which molecular cell routes the tumour uses to grow and spread, we can intervene by targeting that process with medications.’

In the lab, researchers monitor growing tumour cells in mice. Using intravital microscopy, they can see exactly how cancer cells migrate, a process important for metastasis (spreading of the cancer).

In the lab, researchers monitor growing tumour cells in mice. Using intravital microscopy, they can see exactly how cancer cells migrate, a process important for metastasis (spreading of the cancer).


Liquid biopsies
Whether a particular drug works on a tumour depends on the genetic mutations that take place in the tumour cells. ‘A tumour does not consist of identical mutated cells, as we used to believe,’ explains Ten Dijke. When you cut off a piece of the tumour and examine those cells, you don’t obtain a complete picture of the whole tumour. At the moment, we’re doing a lot of research to develop liquid biopsies. This sort of biopsy takes advantage of the fact that some tumour cells always find their way into the blood stream. ‘The idea is that these circulating tumour cells are an accurate reflection of the tumour and that they can provide information about which drugs will be effective in this patient. We are currently implementing this in patient care,’ says Judith Bovée, who is professor of Pathology.


Rare tumours in bone and soft tissue
One of Bovée’s areas of research is sarcomas, which are rare tumours in bones and supporting tissue surrounding organs. In February 2017, she received a Vici grant worth 1.5 million euros to conduct research on this form of cancer. Some 800 people in the 

Netherlands are diagnosed with a sarcoma each year, about 300 of whom are treated at LUMC. When necessary, the tumour is operated on to remove it, but sometimes the tumour is too large for removal or it has spread.

‘We want to study how sarcomas start to develop. So in the lab we produce stem cells with the genetic defect found in sarcomas. Then we look at what exactly goes wrong in the cell that makes it divide uncontrollably. In this way we hope to find clues for new therapies.’

A sarcoma patient talking with the radiotherapist.

A sarcoma patient talking with the radiotherapist.


Existing testing methods
Since sarcomas are rare, it is relatively expensive to develop new medicines for them. A good way to find new and better treatments is to test existing drugs that have been developed for other diseases and other types of cancer to evaluate their effectiveness on sarcomas. That entails less research, because the side effects of these drugs are already known. ‘For example, we are now conducting research together with the Leiden Academic Centre for Drug Research (LACDR) to see whether existing drugs inhibit the growth of sarcomas or render them more susceptible to chemotherapy.’


Bone cancer patient care at LUMC (in Dutch)

Stem cells as cure

Leiden has a long history in the treatment of blood cell cancer. Research to find better therapies never stands still. One of the potential treatments currently being worked on is a ‘living medicine’.


Stem cell transplants
LUMC treats many patients with different sorts of blood cell cancer, including leukaemia, lymphoma and multiple myeloma (Kahler’s disease). LUMC was involved in the first bone marrow transplant, which was carried out on a leukaemia patient in 1968. For this sort of transplant, the patient’s bone marrow is first broken down using chemotherapy or radiation therapy. Then he or she receives new stem cells from a donor. ‘The stem cells that form blood are quite robust,’ says Hendrik Veelken, professor of Haematology. ‘They find their way to the bone marrow and construct an entirely new blood-producing system and a good immune system, which is needed to be able to attack viruses or other pathogens.’ A donor’s immune cells can also attack a pantient's cancer cells that cannot be destroyed with chemotherapy or radiation therapy. This is one of the main areas of research in the Haematology department.

These days it is usually no longer necessary to remove a donor’s bone marrow to be able to harvest stem cells. By giving the donor growth hormones, one can simply take some blood using a needle. The stem cells are then extracted from the blood in the lab and subsequently administered to the patient.


Living medicine
Professor Fred Falkenburg and senior lecturer of Haematology Mirjam Heemskerk are working with their research groups on the so-called living medicine. That consists of donor immune cells that are administered during or after a stem cell transplant to remove any cancer cells left behind. To do this, T-cells – a certain type of immune cell – from the blood of a donor are processed in such a way that they can attack a cancer patient’s tumour cells.


T-cell receptor gene therapy
‘The challenge is making sure that only the malignant cells are attacked and not the healthy tissues. It’s very important to select the right T-cells,’ according to Heemskerk. Her research group has now discovered two T-cell receptors that only react to tumour cells and not

to healthy cells. These receptors act as sensors on the outside of a T-cell, which the cell uses to monitor the environment. When T-cells encounter something dangerous, such as a virus, or even a cancer cell, they can try to render it harmless. ‘We are currently studying whether we can transfer this T-cell receptor to the patient’s own immune cells. We call this T-cell receptor gene therapy.’ This research is initially focused on ovarian cancer, but the same principle can be used to treat other types of cancer.’

By placing the right receptors onto a T-cell (immune cell), T-cells cease to affect healthy tissue, attacking only the tumour. By placing the correct receptors onto a T-cell (immune cell), the cell attacks the tumour.

By placing the right receptors onto a T-cell (immune cell), T-cells cease to affect healthy tissue, attacking only the tumour. By placing the correct receptors onto a T-cell (immune cell), the cell attacks the tumour.

Innovation in treatment and care

Treatment and care for cancer patients is becoming increasingly advanced. For example, surgeons can now perform operations with much greater precision, and therapeutic vaccines are being developed to prompt the patient’s immune system to fight cancer. Work is also being done on better early diagnostics, and much greater attention is being paid to quality of life after recovery.


Early detection
The earlier tumour cells are dealt with, the better. At LUMC lecturer Wilma Mesker in the Surgery department is searching for ways to detect cancer sooner. ‘You might say that we’re looking for a tumour’s signature,’ she says. ‘In blood there are indications that a tumour is growing in the body, even at a very early stage. We are focusing on the proteins that are produced by the tumour, or by the body as a reaction, that find their way into the blood. To do this we use mass spectrometry, a technique one can use to identify molecules. The sooner a tumour is found, the more effectively the patient can be treated, with better chances for survival.’ The test is currently undergoing trials on a national scale on individuals who are genetically predisposed. Mesker hopes to eventually develop a simple blood test that can be administered by one’s family doctor.


Therapeutic vaccination
‘We continue to learn about the important role played by the immune system in cancer patients,’ says Sjoerd van der Burg, professor of Immune Therapy at LUMC. ‘For instance, for some time now chemotherapy has been used to kill cancer cells, but it is only in this century that we have learned that it also has an effect on the immune system. It turns out that chemotherapy sometimes stimulates one’s defence system against the tumour. We are now studying how we can boost this positive effect.’
Van der Burg is working on a therapy to fight types of cancer caused by the human papillomavirus (HPV). 

He is studying whether a therapeutic vaccine triggers an immune reaction against cells damaged by HPV. This experimental medicine has been tested on patients in early stages of vulval cancer. A number of them were completely cured. The same vaccine proved incapable of provoking a strong immune reaction in patients with cervical cancer, but that will soon change. ‘One of the things we look at is how we can combine this vaccine with chemotherapy to produce the strongest possible effect on a tumour that has already developed,’ according to Van der Burg.

The therapeutic vaccine that is the subject of Van der Burg’s research was developed by LUMC and ISA Pharmaceuticals.

The therapeutic vaccine that is the subject of Van der Burg’s research was developed by LUMC and ISA Pharmaceuticals.


Making tumours glow
With most forms of cancer, an operation remains an important component of the treatment. ‘When people are cured of cancer, that is practically always because we have done a good job of removing the tumour,’ says Rob Tollenaar, professor of Surgery. Surgical techniques are constantly improving, with techniques like fluorescence-guided surgery. Leiden researchers are developing fluorescent materials that attach to tumour cells, making the tumour light up and enabling the surgeon to remove it very precisely. They are also looking for substances that make vital tissues more visible, such as nerves and blood vessels. ‘Thanks to these developments, in the future we will be able to perform more effective operations with less damage to healthy tissue,’ comments Tollenaar.

The fluorescent light cannot be seen with the naked eye. By using a camera with a special filter, the surgeon can view the glowing tumour on a computer screen.

The fluorescent light cannot be seen with the naked eye. By using a camera with a special filter, the surgeon can view the glowing tumour on a computer screen.


Brachytherapy, an internal radiation technique, also aims to spare the tissue surrounding the tumour as much as possible. During the operation, the source of radiation is brought as close as possible to the tumour, killing the cancer cells with only minimal damage to the healthy cells. These techniques are already being used in patients with gynaecological tumours. The question as to whether patients suffering from rectal cancer would also benefit from brachytherapy is currently being studied.


Phone consultations
Leiden is leading the nation in evaluating care outcomes. ‘It’s not only a question of whether the operation went well; it also concerns other outcomes that matter to the patient, such as whether the patient’s sexual functions are still intact, and whether the patient can still take the dog for a walk, for example. That’s what we call value-based healthcare,’ says Tollenaar. He is one of the initiators of DICA, an institute that tracks healthcare outcomes. LUMC is heavily invested in e-health, healthcare utilising digital technologies. He gives the example of the phone consultation, where the patient doesn’t have to come to the hospital, but interacts with the physician over the telephone or Skype.


Dutch Institute for Clinical Auditing

Tailor-made medicines

More and more medicines are becoming available that target a tumour’s specific traits. The use of chemotherapy is continually undergoing improvement.


Targeted therapy
Chemotherapy is still a widely used treatment for cancer. The substances used in this technique are targeted at rapidly dividing cells and thus affect not only tumour cells, but also cells in the intestines and hair follicles, causing diarrhoea and hair loss. ‘Now more and more medicines are coming available that specifically inhibit a molecule that the tumour depends on for growth. Which molecule that is can vary and depends on the mutations that have taken place in a cell,’ says professor of Clinical Pharmacy Henk Jan Guchelaar. A treatment using this sort of medicine is known as targeted therapy.


Combination therapies
Professor of Medical Oncology Hans Gelderblom is one of the chief investigators in the DRUP study, in which patients with advanced or metastasised cancer are treated based on the tumour’s specific traits. ‘In this study we are investigating whether medicines that have already been approved for a certain type of tumour are also effective on other types of tumours. What is difficult is that a tumour is usually made up of cells with different traits, whereas a targeted medicine is only effective against one single trait. As a result of the so-called heterogeneous nature of the tumour, a proportion of the tumour cells do not respond to a particular medication and the tumour can continue to grow. This means that in the future more patients will receive combination therapies where multiple drugs are used simultaneously to target all the tumour cells,’ says Gelderblom.

Tailor-made medicines


Improving chemotherapy
Chemotherapy also continues to be used to fight cancer, but with fewer and fewer harmful side effects. ‘We are trying to improve existing chemotherapy by making minor changes to the substances used,’ says researcher and professor Sjaak Neefes. Doxorubicine, for example, works well against cancer cells, but is also harmful to the heart. ‘We are trying to better understand what causes that side effect and are looking to see if we can modify the substance in such a way that it will still work against cancer, but produce fewer side effects,’ according to Neefjes.

Another problem with chemotherapy is that with a portion of the patients, certain substances don’t break down well. Guchelaar explains, ‘Since 2013 we have been giving a preliminary test to patients who will be receiving chemotherapy with fluoropyrimidines. If they aren’t good at breaking down substances such as 5-fluorouracil or capecitabine, we give them a reduced dosage. With this specially tailored chemotherapy we can now prevent half of the side effects. We continue to do research into better tests so we can spare even more people the sometimes serious side effects.’


Medication development
For the development of targeted medicines, Leiden offers unique possibilities. ‘Here we’ve got researchers who can find proteins, chemists who can synthesise substances, a top-notch Good Manufacturing Practice (GMP) facility at LUMC for producing medications and the Centre for Human Drug Research (CHDR), which can test substances on test subjects,’ as Neefjes summarises it. ‘All these partners allow the development of a drug development board that can assist researchers who have an idea for a new drug.’ This makes Leiden the place where the next step can be taken in cancer drug development.


DRUP study
European Lead Factory research project (medicinal chemistry)

 

Cancer and heredity

Some people are predisposed to develop cancer. Mutations in genetic material that increase a person’s chances of developing cancer can already be present at birth. Researchers are closely examining these mutations to learn more about how cancer begins to develop.


Mutations that increase cancer risk
DNA is found in all cells in our body and is divided into genes. Throughout our life, changes occur in our DNA, which we call mutations. These mutations are usually harmless, but when they occur in particular genes they can lead to cancer. Sometimes a person has mutated genes at birth because those mutations ‘run in the family.’ For example, you can be born with mutations in the so-called ‘breast cancer genes’ BRCA1 and BRCA2. This is known to tremendously increase risks for breast and ovarian cancers, but in many other cases of familial cancer it is not clear which mutated gene is responsible. LUMC researchers are studying this issue from a variety of different angles.


Searching for other genes
‘At LUMC we see people with a certain type of tumour occurring in their family more often than you would expect by chance. That’s the case for about 5 to 10 per cent of the cancer patients,’ 

Film star Angelina Jolie had her breasts removed as a preventative measure because she has a genetic mutation in the BRCA1 gene. Photo: People Magazine

Film star Angelina Jolie had her breasts removed as a preventative measure because she has a genetic mutation in the BRCA1 gene. Photo: People Magazine

says Christi van Asperen, professor of Clinical Genetics. ‘So we study whether in that family a mutation occurs in a known gene that can increase a person’s risk for cancer. We find these mutations in approximately a quarter of the families. For this reason, in national and international studies we look for genes that play a role in the development of hereditary breast and ovarian cancer. That entails ensuring that you make a distinction between harmless mutations and those at the root of the disease. We can use this knowledge to correctly inform people with a high incidence of cancer in their family about their chances of developing the illness.’

 

Repairing broken DNA
Marcel Tijsterman, who is professor of Genome Stability, studies heredity at the molecular level. ‘We look at what exactly happens in the cell when a gene mutates: How does the changing of the DNA in a cell cause a higher risk for cancer? For example, when there are mutations in BRCA1 and BRCA2, breaks in the DNA do not repair well. This facilitates additional mutations in other genes, and this snowball effect increases one’s risk for cancer. ‘We 

Cancer and heredity

are also studying other genes involved in repairing damage to the DNA and the extent to which they contribute to hereditary and sporadic cases of cancer. In this way we will come to a complete understanding of the development history of this complex disease,’ Tijsterman explains.


The tumour’s passport
Cancer cells can divide uninhibitedly, but they often also have properties that make them vulnerable. 'The mechanism behind the development of cancer tells us more about those weak spots. We look for strategies to exploit these weaknesses in the treatment,’ Tijsterman explains. He thinks that in the future, researchers will be able to determine a tumour’s entire genome, a tumour’s ‘passport’, so to speak. In this way, cancer patients can receive a custom treatment that is specifically tailored for their tumour.’


Hebon, research on hereditary breast and ovarian cancer (in Dutch)

Experts

  • Hendrik Veelken
  • Sjaak Neefjes
  • Christi van Asperen
  • Marcel Tijsterman
  • Peter ten Dijke
  • Peter Devilee
  • Fred Falkenburg
  • Judith Bovée
  • Rob Tollenaar
  • Sjoerd van der Burg
  • Henk-Jan Guchelaar
  • Maarten Vermeer
  • James Hardwick
  • Ferry Ossendorp
  • Martine Jager
  • Arjan Lankester
  • Lioe-Fee de Geus-Oei
  • Cock van de Velde
  • Martin Taphoorn
  • Carien Creutzberg
  • Corrie Marijnen
  • Pancras Hogendoorn
  • Sylvestre Bonnet
  • Hermen Overkleeft
  • Mario van der Stelt
  • Gilles van Wezel
  • Hans Gelderblom

Hendrik VeelkenProfessor of Hematology / Head of department

Topics: immunopathogenesis of malignant lymphoma

+31 (0)71 5262267

Sjaak NeefjesProfessor Chemical Immunology

Topics: Immunology, infected immune cells

+31 (0)71 526 3800

Christi van AsperenProfessor of Clinical genetics/ Head of department

Topics: Oncogenetics, familiail breast and ovary cancer

+31 (0)71 526 6060

Marcel TijstermanProfessor of Genome stability/ Group leader

Topics: DNA repair, genetic mutations, evolution, cancer

+ 31 (0)71 526 9669

Peter ten DijkeProfessor of Molecular Cell Biology

Topics: Tumour cells, botvorming, ageing

+31 (0)71 527 9270

Peter DevileeProfessor of Tumour Genetics

Topics: Heredity of cancer, cancer prevention, breast cancer, paraganglioma, BRCA1, BRCA2, genetic risk factors, genetic tests

+31 (0)71 526 9510

Fred FalkenburgProfessor of Hematology

+31 (0)71 526 2271

Judith BovéeProfessor of Pathology

Topics: Sarcomas, pathology, tumour development

+31 (0) 71 526 6617

Rob TollenaarProfessor of Oncology

Topics: Churgical oncology, hereditary breast cancer

+31 (0)71 526 4039

Sjoerd van der BurgProfessor of Solid Tumour Immunology

Topics: Immunology, immunotherapy of cancer, tumour immunology, immunomonitoring

+31 (0)71 526 1180

Henk-Jan GuchelaarProfessor of Clinical Pharmacy

Topics: Pharmacy, pharmacogenetics, cancer

+31 (0)71 526 2790

Maarten VermeerProfessor of Clinical Dermatology

Topics: Lymphoma of the skin, skin cancer

+31 (0)71-5262497

James HardwickProfessor of Gastroenterology

+31 (0)71 526 53 64

Ferry OssendorpProfessor of Vaccinebiologie

Topics: Immuunsysteem, vaccinatie, tumoren, infectieziekten

+31 (0)71 526 3800

Martine JagerProfessor of Ophthalmology

Topics: eye melanoma

+31 (0)71 526 3097

Arjan LankesterProfessor of Paediatrics

Topics: stem cell transplantation

Lioe-Fee de Geus-OeiProfessor of Nuclear Medicine

Topics: imaging of tumors with FDG PET/CT-scan

+31 (0)71 526 4376

Cock van de VeldeProfessor of Chirurgical Oncology

+31 (0)71 526 2309

Martin TaphoornProfessor of Neuro-oncology

+31 (0)71 526 2197

Carien CreutzbergProfessor of Radiotherapy of Gynaecological Tumors

+31 (0)71 526 51 20

Corrie MarijnenProfessor of Clinical Radiotherapy

Pancras HogendoornProfessor of Pathology/ Dean LUMC

Topics: Bone and Soft tissue Tumor Pathology

+31 (0)71 526 2559

Sylvestre BonnetAssociate professor

Topics: Biomimetics, light activation, lipid bilayers, metallodrugs, photocatalysis, theology of law, photopharmacology, metallodrugs, liposomes

+31 (0)71 527 4260

Hermen OverkleeftProfessor of Bio-organic Synthesis

Topics: Bio-organic chemistry, immunology

+31 (0)71 527 4342

Mario van der SteltAssociate Professor of Medicinal Chemistry

Topics: Medicinal chemistry, medical marihuana, chemical biology, drug discovery, activity-based protein profiling

+31 (0)71 527 4768

Gilles van WezelProfessor of Molecular Biotechnology

Topics: Antibiotics and resistence, molecular microbiology, microbial interactions in the soil, molecular switches, genomics

+31 (0)71 527 4310

Hans GelderblomProfessor of Experimental Oncological pharmacotherapy

Topics: Sarcomas, phase I research and oncological pharmacogenetics

+31 (0)71 526 3459

Education

Developments in the area of cancer research and new cancer therapies are proceeding at a breathtaking pace. Many types of insight are being gained into various forms of cancer from numerous angles in the degree programmes in Medicine, Biomedical Sciences and Pharmacy in Leiden and in the programme in Clinical Technology, which is offered jointly by TU Delft, LUMC and Erasmus MC.

The half minor in Immunotherapy of Cancer and Molecular Targets and Cancer Therapy are fully dedicated to conducting research to find new methods for treating cancer. Master’s students can train to become medical researchers in the Biomedical Sciences  programme or delve further into drug development in the Drug & Target Discovery programme.

Medical students can complete a master’s degree in Medicine (clinical internships) to become a basic practitioner and to later specialise in an area such as internal medicine, surgery, radio therapy, radiology or nuclear medicine.
Courses offered by LUMC-Campus The Hague discuss cancer in relation to Public Health.

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