How to translate biomarker discoveries into clinical applications
Posted 8th July 2020 by Joshua Sewell
Extracellular vesicles provide an exciting opportunity as a modality for non-invasive biomarkers, which may enable them to be used as biomarkers for tumour metastasis.
Using extracellular vesicles as biomarkers
These vesicles are produced in every cell in the body, whether a tumour or non-tumour cell. In principle, these vesicles can be obtained from biofluids, such as plasma, and utilised to access the molecular composition of a tumour cell.
In 2015 we published papers identifying protein molecules carried by tumour-derived extracellular vesicles which induce pre-metastatic microenvironments. These same molecules could, therefore, be used as biomarkers for predicting tumour metastasis.
In my lab, we are starting to see some progress in differentiating vesicles coming from the tumour from vesicles coming from tumour-associated cells, which are key to tumour biology. This is providing some very interesting information on risk and incidence of metastasis.
There are several populations of vesicles in our biofluids. Therefore, what we are currently developing new methods to identify specific populations of vesicles originating from metastatic microenvironments released by tumour and tumour-associated cells.
The benefits of liquid biopsies for metastasis monitoring
The significant feature of Liquid Biopsies, including the study of extracellular vesicles, allows for non-invasive continuous monitoring of the patient by carrying every form of biomolecule that can be found in a cell (including DNA, RNA, proteins and lipids).
Most patients who already have established metastasis and are undergoing chemotherapy will possibly have to undergo several lines of chemotherapy based on monitoring of their response (or loss of response) to treatment.
While the gold standard for monitoring is currently imaging, it has a significant limitation: no molecular information about the tumour. Our interest in using Liquid Biopsies is that we can understand the molecular composition of tumor and tumor-associated cells, which can be used to instruct clinicians on whether to shift treatment or even which treatment to use next.
Conventional biopsies are made with small pieces of the tumour, but often one doesn’t get access to the whole heterogeneity of cells in the tumour mass. Based on the work of my lab and others, we can see that extracellular vesicle based liquid biopsies give a broader perspective on the composition of tumours by looking at the molecules which are produced by the tumour and tumour-associated cells and found in circulating fluids.
We are currently focusing in proteins specifically present in tumour-derived extracellular vesicles, which we can use to identify and monitor the burden of tumour lesions in patients, including the metastatic ones. We can use the very same sample and method to isolate tumor-derived vesicles, isolate their DNA and get an idea of the mutation profile of the tumour of origin.
The next step: targeting pro-metastatic microenvironments
Back in 2015 we found populations of vesicles that were predicting the formation of these pro-metastatic microenvironments. Now, we are finding vesicles that are produced by these microenvironments. What these means is that we are no longer attempting to predict, but to early detect and monitor the formation of these environments.
There is a crucial third step of initiating therapeutic interventions once we have detected them. This is the focus of a project funded by Breast Cancer Now and Pfizer.
We are targeting the microenvironments, which in this case are pulmonary environments in cases of highly metastatic breast cancer. Our aim is to reverse, or at least to reduce, the risk of lung metastasis.
Something that we are still pursuing as a field is making discoveries in lab setting which are highly applicable in a clinical setting. At the Champalimaud Foundation we are fortunate to have a close working relationship with the clinical department. This means that any discoveries we make in our projects can are potentially one step closer to be tested in clinical settings.
In the area of technological application, we also have some very promising results which could translate into clinical practice. Using conventional methods, the study of a molecule of interest in extracellular vesicles can take as long as 2-3 weeks, depending on the method used. This is obviously not ideal for use for an oncologic patient. We have therefore developed new technologies, which is essentially flow cytometry tailored for vesicles, which has reduced this time to less than three hours.
I would love to our field to continue growing closer and closer to translating our molecular discoveries into clinically useful applications.
Bruno Costa-Silva is a Group Leader in Systems Oncology at the Champalimaud Foundation, Portugal.
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