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Session on Extracellular Vesicles (Including Exosomes) As Diagnostics and Prognostics Highlights Early Morning Events on Final Day of International Society for Extracellular Vesicles (ISEV) 2015 Annual Meeting

The final day of the International Society for Extracellular Vesicles (ISEV) (http://www.isevmeeting.org/) 2015 Annual Meeting in Washington, DC, kicked off with three of the newly-added and highly popular “Meet the Experts” sessions in which world-class experts in a particular area give brief presentations and then interact extensively with the audience in a Q & A session. One of these Sunday sessions was entitled “EVs As Diagnostics and Prognostics,” and was chaired by Fred Hochberg (photo), M.D., a world-renowned expert on glioblastoma, Associate Professor of Neurology at Harvard Medical School, and Attending Neurologist at Massachusetts General Hospital. The two speakers were Clark Chen, M.D., Ph.D., a neurosurgeon/researcher who is the Chief of Stereotactic and Radiosurgery and Director of Medical Education at the University of California, San Diego (UCSD); and Lorraine O’Driscoll, Ph.D., who is Director of Research and Associate Professor of Pharmacology, School of Pharmacy & Pharmaceutical Sciences, at Trinity College Dublin in Ireland. In his brief introduction, Dr. Hochberg emphasized the significance of identifying biomarkers for brain tumors, noting that there are currently four known types of glioblastoma, but it would be “hugely valuable” to have biomarkers that would allow physicians to know the specific subtype as quickly as possible in the disease course. He then introduced Dr. Chen, who he said had a particularly beneficial dual expertise in that he was both a neurosurgeon and a research scientist. The title of Dr. Chen’s brief talk was “Promises and Pitfalls of EVs As a Glioblastoma Liquid Biopsy.” Dr. Chen began by describing the rapid lethality of glioblastoma (GB) and the “opacity of the disease.” Presently, there is no treatment for GB and it is generally fatal within 14 months. It is also very hard to visualize, he noted.

There is an urgent need for biomarkers that might serve as a diagnostic platform for this cancer and it has been suggested that EVs might be useful for this purpose.

Mutations in the IDH1 gene have been associated with one subtype of glioblastoma. Interestingly, patients with a mutated IDH1 gene have an extended survival time of over two years, while patients with wild-type IDH1 gene have a survival time of just one year. Dr. Chen noted that the IDH mutations occur in just one spot on the gene so this makes it easier to identify in analyses.
Extracellular RNA for this gene can be detected in the cerebrospinal fluid (CSF) if the tumor had reached a certain size, but it cannot be detected in the plasma.

Dr. Chen then mentioned that miR-21 is found to be elevated both in glioblastomas and in EVs released from the tumors. EVs with elevated miR-21 could be found in the CSF, but not in the serum. He indicated that the pursuit of miR-21 as a liquid biopsy biomarker for glioblastoma seems very attractive enterprise. He further noted that proximity to the tumor seems to be important, as witness the presence of miR-21 positive EVs in the CSF, but not in the serum.

Dr. Chen then turned to some of the challenges confronting those hoping to develop liquid biopsy markers for diagnostics and prognostics for glioblastomas.

Specific technical challenges he mentioned were normalization; quantitative assessment of EVs, particularly given all the current many different methods for isolating the vesicles; the relative rarity of EVs containing a marker of interest (perhaps 1 molecule in 1,000 EVs, he estimated); and finally, contamination.

Clinical challenges, he said included the collection protocol (sera versus plasma, for instance); medications the patient is taking; storage/transport methods; influence of heparin; venous versus arterial blood; EV subpopulations; cisternal versus lumbar samples; and finally, dependence on the analytic process that will ultimately be used.

Another challenge that needs to be met, he said is comparative analysis of different platforms to determine the best and most appropriate one (could cell-free DNA perhaps be better than exosomes, for instance, he asked). And finally, he mentioned the challenge of implementing evolving technologies.

In closing, he emphasized again the critical need for liquid biopsies, particularly for a devastating and “opaque” disease like glioblastoma.

The next speaker was Dr. O’Driscoll, who immediately impressed with her lovely Irish brogue. At the opening, she also showed a characteristic dash of Irish humor and modesty by saying she was not at all sure she belonged within a group of experts and perhaps some other definitions of the word might be more suitable in her case.

One was that an expert is “an ordinary (wo)man away from home giving advice,” as Irish playwright Oscar Wilde once said. Another was that an expert is “a person who has made all the mistakes that can be made in a very narrow field,” as Danish physics Nobel Laureate Niels Bohr once said. A third was that an expert is “one who knows more and more about less and less,” as Nicholas Butler, onetime president of Columbia University once remarked. And finally, an expert is someone “who used to be a Pert…but now is an EX-PERT!”

Humorous indeed, but not all accurate in Dr. O’Driscoll’s case as she clearly is an expert in the most laudatory of senses and her brief talk on Sunday morning was ample demonstration of this.

Dr. O’Driscoll sought to give the audience a feeling for how exosome and EV research work and enthusiasm in Europe compares with what is happening now in the United States. She emphasized at first the need for standard operating procedures (SOPs) in the field, particularly for the isolation and analysis of exosomes/EVs and the assessment of results. This is certainly similar to the situation in the U.S., where the need for SOPs has been continually emphasized throughout the course of this meeting. Where possible, she said, international collaborative efforts are, undoubtedly, the best way forward.

She noted that there are currently no exosome-based diagnostics or prognostics in clinical settings in Europe, but that extensive research in this area is ongoing.

She noted that in Ireland, there is a consortium called the All Ireland Cooperative Oncology Research Group (ICORG) (http://www.icorg.ie/) and this includes EV research. For example, an ICORG trial is currently accruing for NmU analysis as a companion diagnostic, based on extensive pre-clinical work supported by SFI, HRB, and ICS as Breast-Predict.

Dr. O’Driscoll further noted the recent founding of the European Network on Microvesicles and Exosomes in Health and Disease (ME-HAD) (http://www.cost.eu/COST_Actions/bmbs/Actions/BM1202). The ME-HAD includes 27 EU countries, the U.S., Australia, and six exosome-related companies.

Dr. O’Driscoll then returned the microphone to the moderator, Dr. Hochberg, and he quickly re-emphasized the “huge importance” of standardization in the field. Then he opened the floor to questions.

The first audience member to approach the microphone was Dr. Johan Skog, CSO of Exosome Diagnostics in Cambridge, Massachusetts. Dr. Skog emphasized the need to make every effort to make sure that research work is suitable for use in the clinical setting workflow, otherwise, it might all be for naught. He noted that is often necessary to retrain over and over again in a project’s course, in order to account for clinical acceptability.