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Tobias Weiss splits his work fifty-fifty. He spends half of his time caring for patients – particularly those with brain tumors – in his position as attending physician at the University Hospital Zurich’s (USZ) Department of Neurology. In the other half, he leads a research team at the University of Zurich’s (UZH) Neuroscience Center Zurich (ZNZ). With his research at the ZNZ, Weiss aims to develop new therapies for patients with brain tumors. His reason for splitting his time is clear: “I am confronted on a daily basis with the fact that brain tumors are still one of the most difficult types of cancer to treat.”
Each year, approximately 2,000 people in Switzerland develop a brain tumor, a third of whom develop the most common and aggressive type: malignant glioblastoma. Such people are neurology patients at the USZ, as are individuals with brain metastases. In order to give these patients a better outlook in the future, Weiss and his team conduct research at multiple levels. One of their research priorities is to develop new immunotherapies and test them in clinical studies. They also search for new and improved diagnostic methods that would make it possible not only to detect brain tumors and brain metastases as early and as accurately as possible but also to successfully monitor a therapy’s effectiveness.
In order to reliably diagnose a brain tumor and determine its molecular structure, up to now it has been necessary to perform an operation to obtain a tissue sample. And in order to assess the impact of a treatment, the current practice is to use imaging, in particular magnetic resonance imaging (MRI). Both of these practices have pitfalls. An operation can be risky, and it is often not possible to repeat one, for example in order to detect mutations in tumor cells within tissue samples. Imaging has its limitations as well. If a tumor suddenly appears larger on an image, it is sometimes difficult to determine whether the tumor is actually growing or if a desired, inflammatory immune response to the tumor is occurring.
It would be much easier to use blood samples to detect and monitor tumors. Such liquid biopsies have long been a dream of the medical community. And the fulfillment of this dream is now within reach – thanks to the ability to use different biomarkers in blood (see box).
Weiss and his team use what are called extracellular vesicles (EVs). These tiny particles came to researchers’ attention about 25 years ago. At that time, it was discovered that each cell in the human body releases approximately 1,000 of these particles into the bloodstream and other tissues every day. So our blood is teeming with them. EVs are a kind of copy of the cells from which they originate; they consist of, among other things, DNA, RNA and proteins and are enclosed in a membrane shell. Cells use EVs primarily to exchange information with each other. Since these particles are so tiny, they can easily enter cells and release their contents into them.
The reason EVs are of interest in the field of oncology is that tumor cells also release them. Like other cells, cancer cells use EVs to communicate. For example, EVs influence immune cells so they do not attack cancer cells. To their own detriment, however, cancer cells can be detected by the presence of their EVs, for example in blood. This is because brain tumors also release specific EVs into the bloodstream, a phenomenon USZ researchers are making use of. Weiss’s group is researching how to use EVs to answer the following questions: does an individual have a brain tumor? How large is the tumor? What molecular changes can be found in the tumor?
Weiss’s research group has already studied blood samples from hundreds of USZ patients, in particular those with brain tumors. Their research has shown that it is possible to use EVs to distinguish between individuals who have cancer and those who do not with an accuracy of more than 90 percent. Depending on the type of cancer, the accuracy rate is as high as 98 percent. “This exceeds many of the previous methods but must be confirmed in additional studies conducted in other hospitals,” remarks Weiss.
Now Weiss’s team is focusing on the complex validation process for this method. In order to do this, the team must examine the following questions: Do EV analyses correspond to what can be seen with imaging and in tissue samples? How do EVs reflect the effects of therapies such as radiation therapy, chemotherapy and immunotherapy? The team’s projects are supported by several entities, including UZH’s Research Talent Development Fund (see box), the Swiss National Science Foundation and Innosuisse, the Swiss Innovation Agency. “The interdisciplinary collaboration between the University of Zurich, ETH and the University Hospital Zurich is ideal for moving research in this area forward,” states Weiss. The Swiss Federal Institute of Technology (ETH) is developing, among other things, the technology needed to filter vesicles out of blood; researchers at UZH analyze the vesicles’ molecular signature; and the USZ allows the research team access to patient samples.
One of the goals of this interdisciplinary collaboration is to develop a mobile device that can easily isolate vesicles from blood. A promising patent for such a device is in the works. To advance their research, the team also collaborates with national and international partners. Currently, various hospitals are collecting even more blood samples. These efforts will help determine from which point in time during tumor formation vesicles can be detected. And whether vesicles could be used effectively for other types of cancer besides brain tumors.
“In the next three to five years, we should know what potential these vesicles have,” says Weiss. Ideally, they will bring multiple benefits to the treatment of patients with brain tumors: a blood test is less invasive for patients, can be easily repeated, costs significantly less than medical imaging and makes it possible to more easily monitor the disease’s progression. Moreover, if blood samples can be used to identify the constantly changing molecular structure of tumor cells, it will be possible to develop and adjust targeted therapies that are tailored to individual patients.
Scientists are just starting to understand how extracellular vesicles function. It is clear, though, that they play an important role in how our cells communicate. In the future, their importance could extend beyond oncology to other areas of medicine. Research teams around the world are experimenting with using EVs as biomarkers, for example for neurodegenerative diseases like Alzheimer’s.