‘Individual prognosis is the future of cancer therapy’
Dr Kurt Zanker (55), professor of immunology and experimental oncology, is the Chair and Director of the Institute of Immunologie at the University of Witten/Herdecke. A guest professor at the Gill University, Montreal, and the Beijing Union Medical College, he has recently joined the advisory board of Siro Research Foundation. Prof Zanker has authored two books on immunology and clinical oncology and has 128 original research publications to his credit (impact factor 7). His interest areas include characterization of new molecular targets in cancer cells for therapy, migrating machinery of tumour cells in comparison to immune competence cells and psycho-neuro-immunology. He spoke with Ananth Iyer on new modalities of cancer research
What are the various models available to us in cancer research following the revolution in molecular oncology?
In the past, pathologists looked at tumours in a descriptive way. Now, we are beginning to characterise tumours and its molecular features at an individual level. Molecular biology has today enabled the possibility of individual prognosis, because we can differentiate the characteristics of a tumour in a molecular sense. We need to understand the changes in the molecular machinery that cause these responses in a cell following a stimulus. Various approaches are being studied to target tumours. A cell has four features: proliferation, differentiation, apoptosis (cell death) and migration. In the early days of oncology, biologists told us that tumour cells divide more often compared to normal cells. So, it was rational to discover substances inhibiting cell proliferation. Herceptin and Gleevec are prime examples of substances that inhibit proliferation. Now we know that tumour cells sometimes proliferate slowly. Hence, we also have to understand the other three features of the cell at a molecular level and discover substances, which would inhibit the differentiation or migration machinery of the tumour cells, or induce apoptosis.
What has been the progress on cell differentiation, migration and apoptosis as possible models for cancer therapy?
The possibilities are exciting. For example, cell differentiation is a new target in oncology. The argument is that all cells differentiate from stem cells and this has led to the belief that, at some point of time, due to certain faults, cells change their basic features and proliferate. So, researchers are now finding ways to push the cells towards further differentiation and the more the cell is differentiated the more it loses its potency to proliferate and more it gains the ability to do what it is supposed to do.
The other area that is gaining prominence is apoptosis. There are two ways of defining tumours. The conventional definition of a tumour is a rapidly proliferating cell mass. Conversely, a tumour can also be defined as a mass wherein apoptosis is tremendously decreased. So, a lot of interest is generated to develop agents that induce apoptosis. At the end of each chromosome, there are telomeres. We know that length of telomeres has some influence on the life cycle of a cell. So, if these telomeres are shortened, the cell will automatically die. But, in tumour cells, there is an enzyme called telomerase, which keeps the telomeres longer. So, if we can stop the telomerase activity on a genetic level, we can induce apoptosis.
Another important area of research is cell migration. Migration is a crown achievement in biology. Just imagine; we would not have any living organism if cells do not migrate. There would be no surgery and no immune competence. The same is true for tumour cells. If we can prevent migration of cells out of a tumour, we can then prevent metastases. Importantly, the programmes of cells are interconnected. So, if we can stop migration, then we can possibly stop proliferation too and vice versa. Another aspect of cancer that is being investigated worldwide is the spontaneous regression of tumours.
Do we have any early leads on cell migration?
We have developed a compound. We have done extensive work on cell culture, animal experiments, and phase I study on this compound and we are shortly moving on to phase II studies. It is not a very specific compound but we know that it interacts with the migratory machinery of tumour cells. But, the problem area is that this substance has to be administered in high concentrations if it has to trap certain molecules. However, the positive message is that there is no toxicity reported so far even in high concentrations. Another advantage is that the substance can be orally administered.
What is the best approach to address cancer – to target the immune competence or the tumour – since cancer is an immunogenic disease?
This is a million-dollar question. I think we have to adopt a multi-step modality with emphasis on patient care and response. When immunology came up, we were very enthusiastic. But, we now see that immune cells are tolerant to tumours. We are beginning to learn a new paradigm in immunology. We now know that immune competence cells cannot differentiate a normal cell with a tumour cell. We know that they recognise tumour cells as foreign objects but they do not consider them as a danger. Hence, they do not react. The immune system is not active if there are large number of cancer cells. The question is why are they tolerant. This is a vital area of research where we will have to develop mechanisms to break the tolerance of the system against the tumour.
Do stem cells find their application in oncology?
Stem cells are proven to be useful to replenish the bone marrow loss after chemotherapy. The implication of stem cells in cancer is an interesting and difficult preposition and I have my own opinion. At this moment stem cells in oncology have no curative role. All we know now about stem cells is that they give out signals to activate cell differentiation. Interestingly, a tumour mass also sends out signals. So, if we can arrive at a situation where we can find out what signals these stem cells need to differentiate between a heart muscle, a neuron and tumour cells, then we can possibly cut cell proliferation, induce apoptosis and also inhibit migration. Also, we have to find out whether stem cells can achieve tumour regression. There is a possibility. My interest is to identify signals that turn on and off the migratory and proliferating machinery of the stem cells.
There are evidences suggesting the role of psychological events on cell proliferation. Could this lead to any breakthroughs?
It is a very interesting area of research. It is important to take into account the psychological impact on the patient (tumour). We have identified the presence of neurons in tumours. It is like a life within a life. These neurons lead the tumour cells. We have also observed that substances such as epinephrine and norepinephrine stimulate tumour cells to migrate from the tumour. In other words, these agents turn on the migratory machinery. This is corroborated by findings in animals. If animals are exposed to high levels of stress, the tumour in them explodes. This is because animals have high concentration of epinephrine and norepinephrine. This is an interesting point for us because we often think about psycho-neuro-oncology. Psychological event has something to do with the outcome of a disease though it is not easy to prove this. For example, we do not have many coping mechanisms to psychological events. We have to learn that. For instance, we, in the modern civilization, have forgotten about the flee reflex when faced with imminent danger or provocation. This develops chronic stress, which, in turn, could lead to chronic levels of neuroactivity through epinephrine, ultimately resulting in cell proliferation. But, we have to prove this. This indicates that we cannot afford to ignore cancer prevention strategies.
But are prevention strategies workable?
Prevention strategies like non-smoking and nutrition can cut down the incidence of cancer by 40 per cent worldwide. Let me give you a European prospective. The first attempt should be to see whether we could prevent the carcinogenesis. The first step is stop smoking. The second is to eat specific diets because each diet, which we eat, are at the very end molecules and these molecules are not only for energizing your body but also for feeding your body with signals. In plants, for example, there are so called secondary plant products. Plants themselves regulate the metabolism, growth and apoptosis of cells. Cell culture and animal studies show a lot of new plant molecules as cancer protective. If we choose diets which include these molecules, then you have greater chance to prevent cancer. But to find that out, we need epidemiology studies. We look at certain population that are less cancer prone to others. For example, in Japan, people who grow and consume green tea are less prone to cancer than people living in Tokyo. Again, Japanese women eat a lot of soya, which is rich in phytoestrogens. But, if the Japanese women migrating to the US develop the habits of the immigration country, then the risk ratio to develop cancer in the next generation increases. This gives us a clue on what sectors of plants we have to look into.
You say that it is possible to achieve individual prognosis for cancer. Are you suggesting that oncology research is moving to individualised therapy?
Yes, individual therapy is the future of cancer. Oncology research is moving away from cohort studies to individualised therapy. We have to individualise therapy and every time we recommend a therapy, we have to measure its outcome at an individual level. But, individualised therapy demands exact laboratory procedures for molecular diagnostics. This is achievable since molecular biology has exploded the targets and it is realistic to assume that there will be a lot of diagnostic tools developed to identify these targets at an individual level. However, the challenge is the clinical treatment, which is a very slow mover. The gap between the molecular biology and clinical outcome is widening. Hence, we have to create new parameters in clinical research where we can decide the efficacy of a particular therapy at an individual level. It is a difficult challenge.