Page 59 - Read Online

Page 10 of 18 Happel et al. J Cancer Metastasis Treat 2020;6:32 I http://dx.doi.org/10.20517/2394-4722.2020.71

C Biofluid Number of studies
Blood 23
Bone Marrow 2
Lymph 1
Plasma 4
Serum 7
Saliva 1
Urine 7
Semen 1

Figure 3. Current clinical studies evaluating the use of exRNA and exosomes as cancer biomarkers. An advanced search for query terms
(“extracellular RNA” OR exosome OR exRNA OR oncosome) AND biomarker focused on cancer as a disease model, was performed on
ClinicalTrials.gov on 11 May 2020. The search was restricted to recruitment statuses on recruiting, not yet recruiting, active, not recruiting,
completed, enrolling by invitation, and studies of unknown status. The search returned 45 studies which are summarized in Figures 3A-
C. A: A world map shows the locations (in red) of all clinical studies evaluating the use of exRNA and exosomes as cancer biomarkers.
The numbers indicate the clinical studies in each location; B: clinical trials were grouped by general cancer type and the number of studies
focused on each cancer type are shown. Projects that did not specify cancer type were grouped together as non-specific cancer; C: the
clinical trial data was parsed for the types of biofluids used in each study. Some studies examined multiple types of biofluids while other
did not include biofluid sampling. The table represents biofluids examined in all 45 clinical studies

plasma is utilized for 34 out of the 45 clinical trials investigating the potential of exRNA and exosomes as
clinical biomarkers, representing 17 different cancer types. Not surprisingly, urine is the biofluid of choice
when investigating biomarkers for prostate cancer. However, clinical studies are also exploring the of use
of urine as a biomarker for thyroid and kidney cancer. Saliva is an emerging biofluid that is inherently easy
to collect, and, has been shown to reflect the spectrum of health and disease states found using serum [56,57] .
While there is only one clinical trial in this dataset using saliva for biomarker discovery, it is conceivable
that emerging technological advancements will move saliva into the forefront as an accurate and reliable
biofluid for molecular diagnostics.

Most studies investigating the use of exRNAs as biomarkers have focused on miRNAs, and indeed 12 of
the 45 clinical trials in this dataset specifically examine the use of miRNAs as cancer biomarkers. However,
two studies investigate mRNA as exosomal cargo and a molecular biomarker in cancer. Further, there is a
clinical study looking at circular RNA (cRNA) in pancreatic cancer, and a study exploring exosome derived
lncRNA in ovarian cancer. Notably, most of the clinical studies did not indicate a specific exRNA target.
Overall, this data demonstrates widespread utility of exRNA and exosomes as clinical biomarkers across a
spectrum of biofluids and cancer types.

NIH-supported research focused on exRNA and exosomes as biomarkers in cancer
The NIH supports many pre-clinical research projects focused on the use of exRNA and exosomes as
biomarkers in cancer. To understand the breadth and type of research funded by NIH, we explored the
Research Portfolio Online Reporting Tools Expenditures and Results Tool (RePORTER) using the website:
https://projectreporter.nih.gov/reporter.cfm. An NIH RePORTER search for exRNA and exosomes as
biomarkers in cancer found 138 projects that have been funded by NIH between 2010-2020, which is
summarized in Figure 4A and B. NIH funded projects were grouped by funding type and the number
of awards for each funding type can be found in Figure 4A. A large majority of these studies (87 out of
138) were research projects. However, the number of research training and career development awards
indicate a growing number of trainees entering the field. The NIH Common Fund’s Extracellular RNA
Communication Program (ERCP) funded eight projects focused on exRNA and exosomes as biomarkers
in cancer. NIH Small Business Innovation Research (SBIR) awards make up 10 of the 138 projects.
These SBIR awards included funding to Tymora Analytical Operations, Cognext Diagnostics, Abtelum
Biomedical, Nanomaterial Innovation, Biofluidica, Nanoview Diagnostics, Accure Health, Ascent Bio-Nano
Technologies and Microsensor Labs.