‘I’m really hopeful that we can develop better therapies for both dogs and people’
Working together on a new treatment for lymphoma
Lymphoma is quite common in dogs, but also in people. Patients are treated with chemotherapy, but the cancer often returns over the course of time. Alain de Bruin, Professor of Pathobiology in Veterinary Medicine, and , internist-haematologist and Professor of Haematology at UMC Utrecht, want to jointly develop a new therapy against lymphoma. The idea? Combining chemotherapy with a frequently used drug against breast cancer.
Lymph glands assist our immune system. They are the glands that swell up somewhere in the body if there is an infection, for example a throat infection. The immune system then attacks the infection and tries to suppress the inflammation. That happens with the help of white blood cells, so-called B lymphocytes and T lymphocytes, which die once they have completed their “immune task”.
Never in a single place
However, sometimes this goes wrong and lymphocytes change into cancer cells. That is when lymphoma develops. ‘Lymphoma is a cancer of cells from the lymph glands’, explains Monique Minnema. ‘As a result of one or more mutations, B cells no longer die, and an enlargement of a lymph gland occurs. People feel that as a non-painful lump.’
What makes lymphoma so special is that it is never just in one place. Minnema: ‘Our immune cells are trained to move throughout our body, from your toe to your ear. They continuously swim through our body and use the circulatory system and bone marrow to do so. Lymphoma can be found at several locations, but usually in the lymph glands, the bone marrow, liver and spleen. We do not usually find it until it has spread to more than one location. It is a systemic disease that we cannot treat locally with radiotherapy or surgery, but only with chemotherapy. That is the only therapy that passes through the entire body.’
PET CT scan of a lymphoma patient. A PET CT scan makes use of the increased uptake of glucose by cancer cells. Administering radioactively labeled glucose makes tumors visible. On this scan, on the right, in the patient’s neck and armpit, enlarged lymph nodes are visible, and below the right collar bone, a large tumor. The patient received treatment and has been cured.
Comparable with people
Lymphoma is also common in dogs. Actually, it is the most frequently occurring form of cancer in dogs, irrespective of the breed. ‘The disease is very similar to that in humans’, says Alain de Bruin. ‘In dogs, we also see a clear swelling of the lymph glands, especially in the neck. That is often what we first see in people too. For dogs, we also use chemotherapy to treat this disease.’ Chemotherapy is rarely given at veterinary practices, but usually happens in specialised clinics such as the ľϸӰ Clinic for Companion Animal Health in Utrecht. Therefore the veterinary oncologists of the university clinic, Maurice Zandvliet and Erik Teske, see patients with lymphoma relatively often. They play an important role in the research team for cancer therapy.
Many people die from cancer. I find it satisfying that through my work, I can contribute to the development of new therapies against this terrible disease.
New therapy
Minnema and De Bruin are now working together to develop a new therapy for lymphoma. ‘We do not want to do just fundamental research. We would also like to set up clinical studies together’, says De Bruin. ‘We have submitted a joint research proposal for this. In Utrecht, Monique is one of the specialists in this area, and that is why we invited her to take part in this project. We first of all want to set up clinical studies in dogs and, later on, in people too. The dog is a good model for humans.’
‘What attracted me to this research is whether we can translate knowledge about the lymphomas that naturally occur in dogs to people’, says Minnema. ‘That really intrigues me. We mainly work with cell lines, but the results from the laboratory rarely work in people, and that really shocked me. They call that the Valley of Death. As lymphomas in dogs and people are very similar to each other, I see this research as a step towards treating people. Do discoveries made in dogs have a higher chance of succeeding in people? In my view, this is a genuinely unique project.’
Dog as (intermediate) model
The basic cancer research often takes place with mouse models, but they frequently fail to work when translated to humans. De Bruin: ‘Only five to ten percent of the preclinical mouse models can be translated to people. One of the reasons for this is that mice are more or less genetically identical. They live in the same environment and receive the same food, and that means it is relatively easy to find differences in a therapy. However, each person is different in terms of genetics, nutrition and his/her environment. Then it is harder to detect the differences in therapies. Dogs are a good intermediate model: they acquire the same disease spontaneously, are treated in the same manner and live in the same environment as people. Differences in dogs can probably be more easily translated to people, and American studies have already shown that in part. I’m really hopeful that we can develop better therapies for both dogs and people.’
What does your new therapy look like?
De Bruin: ‘We want to take the standard treatment for lymphoma and combine it with a drug that is intended to strengthen the effect of the chemotherapy. Chemotherapy causes a lot of damage to the DNA of tumour cells, and as a result of this, the cancer cells die. That mainly occurs in rapidly dividing cells. Cancer cells try to repair the damage as quickly as possible and often become resistant to chemotherapy. This drug inhibits the repair of the DNA damage in cancer cells, as a result of which the DNA damage accumulates and the cancer cells die faster. Consequently, the chemotherapy is more effective.’
What sort of drug is this?
‘It is a frequently used drug against breast cancer, the cyclin-dependent kinase inhibitor CDK 4/6. In combination with another therapy, that is reasonably successful. We now want to use CDK 4/6 for lymphoma too. Preclinical studies in cells and mice have revealed that this is effective in combination with chemotherapy: on the one hand, to inhibit cell growth, but also to hinder the repair of DNA damage. Now we want to take the next step.’
‘We’ll start with a small group of patients, about twenty dogs’, continues De Bruin. ‘If that works, then we can set up a clinical study for people. Another advantage of this approach is that no experimental animals are required. We can try it out directly on dogs in the clinic, and they will also benefit from this. Dogs live longer and will perhaps require less chemotherapy.’
Could this combination work with other forms of cancer?
‘Most definitely! Especially because chemotherapy is given for many types of cancer. More than hundred studies with CDK 4/6 inhibitors for different types of cancer have been published but never in the combination that we want to try here for lymphoma. That is what makes our project unique for both veterinary medicine and human medicine.’
I cannot always keep somebody alive, but we fight together to do so as long as possible and with the best possible quality of life.
How did you find each other?
‘Inga Wolframm [head of fundraising and manager Friends of VetMed, Ed.] played a large role in that’, answers De Bruin. ‘Inga came up with the idea of seeking collaboration with human medicine. She also helped with finding the research funders.’
Where does your fascination for cancer come from?
‘That did not occur automatically in my case’, says Minnema. ‘I gained my PhD for research on blood coagulation and then I became an internist and haematologist. I really had to think carefully before I entered the field of cancer research, because it is both tough and emotional. But in the end, I’m really pleased that I chose this discipline. Now I only do cancer research.’
Minnema is fascinated by the huge number of developments in this discipline. ‘Sometimes you cannot keep track of how many fantastic results there are; it’s like being a child in a sweet shop! Furthermore, you have intensive contact with the patient, and so you know your research is making a real difference. Patients are very motivated for treatment, and I have already known some of them for ten years. You build up an intensive relationship and they know my children by name, so to speak. I cannot always keep somebody alive, but we fight together to do so as long as possible and with the best possible quality of life. It is this deep dimension in the research that attracts me so much.’
I really had to think carefully before I entered the field of cancer research because it is both tough and emotional.
Does the same hold for you, Alain?
‘I’ve always wanted to understand how cells divide. Which mechanisms underlie that? I do the research together with Bart Westendorp (cell biologist) and our research team. In the case of cancer, we often see mutations in genes that play a role in cell division as a result of which the cell starts to grow uncontrollably. Why does that happen? Many patients are treated with drugs, but the cancer often returns. Why do some cancer cells die during therapy, whereas other survive? How does resistance develop? That’s what we want to understand. We want to inhibit the repair mechanisms of cancer cells to make the cancer therapy more effective.’
‘One in three people develop cancer and many people die as a result of it’, continues De Bruin. ‘Friends, your family, cancer affects everybody. It is in the public interest that we do something about this. I find it satisfying that through my work, I can contribute to the development of new therapies against this terrible disease.’