Prof. Dr. Guus van Dongen

Guus van Dongen leads the section of Preclinical Imaging of the Department of Radiology and Nuclear Medicine at the VUmc. His research focus is the experimental detection and targeted therapy of cancer. He also leads the project to establish the VUmc Imaging Center Amsterdam, a fully-integrated, advanced imaging facility which will accommodate all preclinical and clinical imaging activities of VUmc, including those of TracerCenterAmsterdam and BV Cyclotron VU. One of Prof. van Dongen’s main research lines is the use of targeted drugs, such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), for disease detection and therapy. In this field, he introduced the techniques of immuno-PET and TKI-PET, for imaging of radiolabeled mAbs and TKIs, respectively, as well as photoimmunodetection.

Change in the field of PET research
“In my own biography you can see an interesting change in the field of PET research: In 2002, I started working as a professor at VUmc, Amsterdam. It was around this time that I really got into using Zirconium-89 as the labeling agent for monoclonal antibodies. Its physical half-life of 78.41 hours makes it the perfect match for mAbs, since the time it takes for a mAb to target a tumor is typically two to four days. Production of Zirconium turned out to be straightforward, and it could be produced in large quantities and at reasonable cost. The only thing we did not know at the time was whether it would be possible to label mAbs with it. It took us three years to find a robust way to label the mAb with 89Zr. Our first labeling procedure was fairly complex – there was nothing commercially available for doing this, so you had to do everything yourself in the lab. Yet we managed to master the individual steps, published them and received fairly good feedback. Soon after that we could do our first preclinical trials and show that it was indeed possible to get labeling properties with 89Zr that would not influence the pharmacokinetics and biodistribution of the mAb.”

Amazing results
“From these first trials, we just got amazing images. They would literally say more than a thousand words. Everyone in our team was blown away with them. So, I went to conferences all over the world, and showed them off. I was totally convinced that, with 89Zr, we would be able to revolutionize the world of molecular imaging. And I did everything that was within my powers to say so. Typically, I started by saying that I saw Zirconium as a once-in-a-lifetime discovery. And then I went on to put down the alternatives, most importantly Copper-64 (64Cu).”

Swearing in church
“But this strategy didn’t work out so well. People were not taking me seriously. The more excited I got, the more skeptical the reception was. At the time, the research consensus was that 64Cu (T1/2 = 12.7 h) would be the dominant positron-emitting radionuclide for decades to come – not just as a useful radiotracer for positron emission tomography (PET), but also as a radiotherapy agent. Everywhere people started running small biomedical cyclotrons, developing new methods for the efficient production of high specific activity 64Cu, and there was a lot of funding available for finding new labeling techniques. So, when I talked about 89Zr, this was seen as nothing less than swearing in church.”

“I felt misunderstood. All kind of negative powers within the field of research started to grow. Some thought that I was more promoting my own commercial activities than I was doing serious research. Others thought I was just an industry-backed 89Zr evangelist. Some peer reviewers would wipe the floor with articles from our group as soon as they saw the word ‘Zirconium’.”

“Fortunately, this has all changed now. There are many groups working on 89Zr and 124I at the moment. There is a continuous stream of very promising clinical trials. And the industry also made a U-turn – Genentech and Roche are regular visitors in our lab. Recently, several companies have started the commercial production of the chelate that is needed to label antibodies with 89Zr, which now makes labeling a very simple procedure. What I see in the field now is an unprecedented momentum for 89Zr. Not just in oncology, but also for research on for instance neurodegenerative (e.g. Alzheimer’s), immunological and cardiovascular diseases.”

“What I learned from this experience is that you can have your Eureka-moment, but in the end, you need your peers to trust you. For this, it is absolutely necessary to be completely open and transparent about the different roles – as researcher, as board member of a company, or an advisor for the industry. Also, I learned that polemics is not a good strategy for changing the world. If you truly believe that your brainchild makes a difference, then you have to cooperate with people. Treat antagonists dispassionately. Have them thoroughly test your results. If they validate your work, then hope they will publish it. And, with some luck, you will end up with evangelists.”

“I have been very lucky to find such evangelists in the Netherlands and Belgium in the very early stages of our work. The VU Medical Center has proved invaluable for our research, but also the University Medical Center in Groningen, the St. Radboud Medical Center in Nijmegen, and the University Hospitals in Brussels and Antwerp. These have enabled us to start clinical trials quite early on. And the results from these trials had an impressive impact, as they were much better than we had expected”.

“One of the things I am currently very excited about is the founding of the European infrastructure for translational medicine EATRIS. EATRIS aims for faster translation of basic research into innovative products. What I hope we can accomplish with EATRIS is a rising awareness that, in drug development, no one can do everything by oneself and imaging is a crucial component for this. You have to have academic medical centers, small and large industry, and patient groups cooperate. Take for instance a company that makes PET-scanners, such as Philips. For medical innovation, the company has always been secretive. This way, it takes about 10-12 years to develop new scanners. But what if innovation cycles must reduce dramatically? In order to keep up with the general pace in the field, and to make sure that you don’t develop tools beyond clinical reality, you need to develop such hardware with the people who make new tracers, with experts in the clinical application, and so on.”

EATRIS will offer new ways to break through the isolated cultures of industry, academic centers and biomedical research. I see huge challenges in this effort: you need to bridge the gap between all actors. The physical gap will be the easiest part, but you also have to find a solution for the fact that all these actors speak different scientific languages. So, how to create an interdisciplinary knowledge-domain that will lead to more innovations?”

Paradigm shift
“On the one hand, academics are generally not sufficiently aware of the regulatory and economic hurdles that have to be overcome when bringing a product to the clinic, while only a few centers have the financial resources, infrastructure and expertise to embark on this risky journey. On the other hand, the pharmaceutical industry is facing worrying challenges in the pursuit of economic value and medical impact in the R&D process. Of every ten drugs that enter clinical testing, only one will make it to the market. Only a small proportion of the indicated patients have objective benefit of treatment with the registered products, varying from 20 to 50% for different disease areas. So, without a dramatic paradigm shift, new drug development will further stagnate. There are simply not enough patients to test all the newly designed drugs, while there is a tendency that patients become more critical with respect to participation in clinical trials with experimental drugs.”

Grand Challenge
“I think this is one of the ‘Grand Challenges’ that our society faces – to create the research infrastructures that will bring together researchers, industry, funding agencies, politicians and patient advocacy groups to act together as an innovation hub. Imaging and tracing have an essential role here, because they increase the speed and reduce the cost and risk of products in development. This will be essential for developing truly personalized – or ‘high precision’-
medicine and healthcare.”

Prof Guus AMS van Dongen, PhD, biochemist – VUmc, Amsterdam

Prof van Dongen accomplished his undergraduate and PhD studies in Molecular Cell Biology at the University of Utrecht. In 1989, he started work at the VUmc focusing on experimental detection and therapy of head and neck cancer using targeted drugs such as monoclonal antibodies. Here, he introduced the immuno-PET, TKI-PET and photoimmunodetection techniques, and has brought more than 20 antibody conjugates into first-in-man studies.

He is currently full professor at the VUmc and leads the section of Preclinical Imaging of the Department of Radiology and Nuclear Medicine at the VUmc. Within VUmc, he also coordinates the research program Disease profiling (Cancer Center Amsterdam). He is project leader for establishing the VUmc Imaging Center Amsterdam, which will accommodate all preclinical and clinical imaging activies of VUmc including the activities of TracerCenterAmsterdam and BV Cyclotron VU. Within EATRIS, he coordinates the platform on Imaging and Tracing with many top European PET centers involved. His further activities include reviewing, advising and leading various top projects and programs, both within the VU/VUmc and across Europe.