An international team of researchers works on optimising radiotherapy with individualised methods of treatment. The project is funded by an ITN Grant and coordinated by Martin Pruschy, Professor for Molecular Radiobiology at the University of Zurich: a glance into the future of cancer treatment.

The monumental radiotherapy equipment used for research purposes stands properly insulated far below the ground in the depths of the Irchel campus university building. For most of their work, however, the team of Professor Martin Pruschy can use the bright offices and laboratories of a first floor.

Martin Pruschy heads the Laboratory for Applied Radiobiology, which is affiliated to the Department of Radiation Oncology of the University Hospital Zurich. Radiation oncology is one of the main pillars of cancer therapy. More than 50% of all cancer patients undergo radiotherapy during the course of their disease. At the same time, radiotherapy per se is very interdisciplinary: dependent on physics, linear accelerators, imaging techniques – only by means of computed tomography or magnetic resonance imaging a tumour can be located precisely. Key element, however, is always biology because it is needed to understand the processes inside the tumour. And: parts of the normal tissue are always also exposed to radiation. This is why the processes in the healthy tissue have to be analysed as well.

Yet, research in the area of radiobiology is much less prevalent than for example molecular oncology research. This is the starting point for the project coordinated by Pruschy and funded by an Innovative Training Network Grant of the Marie-Skłodowska-Curie-Actions: the international network joins eight labs and thus creates one large laboratory. In this way, much more research can be conducted compared to what would be possible for the individual laboratories by themselves.

The ITN programme runs for four years and is called Theradnet, short for International NETwork for training and innovations in THErapeutic RADiation. 15 PhD students at eight universities in six European countries thereby distribute their research work on three topics.

Different radiation, different effects

Some of the researchers are dedicated to tumour sensitisation, i.e., the influence of radiation quality of photons and protons on molecular cell responses. In addition to classic photon radiotherapy, there is an increasing approval of novel radiation therapies in cancer treatment. For example, the Paul Scherrer Institute in Villigen works with proton irradiation and in Heidelberg as well as in a few other centres around the globe carbon ion particles are also used for irradiation. These two types of radiation have physical benefits: the proton beam targets the tumour with maximal precision and the radiation dose is not deposited in the tissue located behind, while photons radiate through the tumour and therefore also affect the healthy tissue behind it.

Proton treatment triggers different processes at the molecular level than photon treatment. For this reason, the researchers study why certain tumour cells show a better or worse response to proton irradiation than to photons. For example, when different repair mechanisms of the DNA are used to repair photon or proton damages, one could possibly identify which tumour and patient, respectively, is better suited for this or that type of treatment.

Preclinical and clinical studies

The second research project deals with FLASH radiotherapy: the usual dose rate of photon irradiation is two grays within two minutes per day – 1 gray corresponds to 1 joule per kilogramme of absorbed energy. The new FLASH therapy is an ultrafast radiation treatment that is to administer a dose of more than 40 gray per second. This form of therapy is still in its preclinical phase. It has various advantages. For example, it was demonstrated that this highly dosed and at the same time ultrafast form of radiation damages the normal tissue affected by the radiation process to a lesser extent. It is now important to understand the thereby occurring biological processes and to then transfer the therapy into clinical practice.

The third research project focuses on resistances and pharmaceutical agents. Depending on the duration and type of irradiation the tumour develops defence mechanisms against the treatment and side effects occur – both good and bad ones. For example, a traditional fractionated radiation therapy can remedy the usually existing oxygen depletion inside the tumour, which enhances the tumour’s response to the treatment. Other processes take place in the irradiated tumour vessels in case of irradiation with higher dose per fraction that can now be administered thanks to the available technical development. Hereby, oxygen depletion is increased instead of reduced. The higher dose per fraction is hence allegedly harmful; however, it is compensated by other biological processes inside the tumour. Based on the understanding of these processes, novel concepts for radiochemotherapy can be developed.

Martin Pruschy summarises: «By the development from low to high dosed fractionated irradiation, the newly induced processes showed that the immune system plays an additional role for the success of radiotherapy. The next step will be to fully benefit from these immunotherapeutic possibilities and to combine them with radiotherapy.» For example, the success rate for locally advanced lung cancer was increased hereby from 20 to 40 percent.

Certainly, each of these developments consists of constant but small steps towards enhanced chances of survival and recovery, Pruschy adds. The development of chances of recovery in the case of breast cancer exemplifies it well. Before the Second World War, the survival rate was at ten to 20 percent – today, 70 years later, it is at 80 to 90 percent.

Exchange between young researchers

Not all of the researchers have access to all of the equipment relevant for these research projects. For example, there are no facilities for FLASH therapy in Zurich. However, within the ITN programme, the PhD students can travel to Paris for two months and test their research results regarding said therapy on site. Or: someone in Brussels developed something in vitro at the cellular level and would like to assess it in vivo. Hence, he travels to Zurich for a few months, where there is a corresponding small animal irradiation device.

Every PhD student should be able to complete two to three stays abroad at various partner universities. The non-academic partners also partly offer study opportunities. Part of the network are larger industrial companies such as Varian, a company that produces linear accelerators, but also start-up companies interested in connecting with representatives from the preclinical research in radiobiology.

As the coordinator of the project, Martin Pruschy currently dedicates one entire day per week to Theradnet – including administration, logistics as well as the constant motivation of all participants despite Covid restrictions. To this end, he gets creative: after a recent three-day meeting, every participant of the programme received a printed mug with a screenshot of everyone during the Zoom meeting. A small consolation for the fact that physical meetings cannot be held as planned two to three times a year.

Already from 2015 to 2019, Pruschy participated in an ITN project: 14 students collaborated in this project called Radiate. «Thereby, a young generation of radiobiologists are trained who will advance and determine the development in Europe in ten to 20 years – which is the basic idea of a Marie Skłodowska-Curie project,» he emphasises.

Experience and trust

What is the motivation behind making teaching one of the top priorities of his work for the second time already? Martin Pruschy laughs and remains modest. He has his own SNSF and Innosuisse Grants, he says. In 2014, he was asked to participate in the first Marie Skłodowska-Curie ITN Grant. «In doing so, I quite easily received two PhD students for my own research,» he recalls. It was not until later that he realised that the PhD students in such a programme invested a lot of time in knowledge transfer and networking. However, the quality of the research work was not diminished by the many travels and meetings within the framework of the ITN project and could be compared to the works of other PhD students.

Theradnet roots in the ITN Grant project Radiate: hence, the Principal Investigators, the main actors, were already familiar with one another, there was trust and respect. And: «Everyone already knew that they would profit from this kind of research collaboration,» the coordinator assures.

Admittedly, the expenditure of time should not be underestimated, he adds. Pruschy relies on the assistance of a network manager for his coordination work and continues to be supported closely by EU GrantsAccess. This office co-prepared the proposal and shaped the interdisciplinary aspects mainly in the non-scientific part of the project.

Pruschy’s advice, consequently, for everyone planning a similar project is to set up a good management team. What is more, he closely collaborates with two other Principal Investigators: the 1,000 hours invested in preparing the proposal for the Grant, he recalls, were divided equally between the three initiators – Professor Verena Jendrossek of the University of Duisburg-Essen, Professor Ludwig Dubois of the Maastricht University and Pruschy himself.

ITN proposals have small chances of success

For continuity reasons, more or less the same people were chosen for Theradnet 2019 as for Radiate. Hence, the partners were picked by means of personal contacts but also based on their track records and distribution across the entire EU area in order to further develop the potential. Among the non-academic partners besides the industrial partners are one political organisation, patient organisations as well as a publishing house.

Only six percent of all ITN Grant proposals are successful. And there were several reasons against Theradnet as well: the programme seamlessly followed upon Radiate and a person from Switzerland is in charge. It worked out anyway. Pruschy considers his work as part of his responsibility towards research and ultimately towards the patients concerned. «If this kind of project is coordinated from Zurich, it is important for Zurich as a research location and the University of Zurich’s reputation,» he adds.

Interview with Martin Pruschy (in German)