underexpressed proteins that are detected by IMS significantly improved the
chances of this technology to be used for personalized cancer patient profiling.^93
The use of both above-presented strategies for following of the cancer treatment
and definition of patient’s prognosis fulfills some of the goals presented above—it
(1) helps to identify the needs of the individual patient and identifies biomarkers by
the use of specific antibodies or IMS, (2) helps to match the right personalized
treatment, and (3) improves the performance of clinical trials through molecular
profiling. However, it fails to fulfill two main goals—the tissue sampling is a
relatively invasive treatment, and the following analytical work is time and material
consuming (see, e.g., Drake et al.^94 ). It means that the work towards detection and
validation of new biomarker candidates, especially the ones that can be analyzed in
body fluids, is still the essential need, not only in order to reach optimal personal-
ized cancer treatment but also for the personalized treatment of other diseases.^95
Already in 2002, the prostate specific antigen (PSA) and other prostate specific
peptides and proteins in human serum (or plasma) were discussed as possible
biomarkers in order to distinguish prostate cancer from benign prostate hyperpla-
sia.^96 However, the doubts about the validity of PSA as a biomarker for prostate
cancer and numerous sources of sample bias have been the introduction into the
abovementioned discussion about the validity of specific proteins (and protein
forms and corresponding peptides) as disease biomarkers.^97 It has to be stressed
repeatedly that special attention is necessary when biological fluids are used for
biomarker discovery. Firstly, the concentration of proteins and peptides comprising
the complex blood proteome spans sometimes as much as 10 orders of magnitude,
and 20 highly abundant proteins are present in amounts that are more than 90 % of
the protein content in the sample.^98 Consequently, it is a big challenge to detect a
biomarker candidate of clinical interest that is present at concentration in the very
low part of the scale. Recent results show that this goal can be reached by the use of
miniaturized, high-throughput robotic devices.^99 Additionally, highly sensitive
mass spectrometers and new development programs for result evaluation enable
detection and even quantification of thousands of proteins that are present in the
sample in trace amounts.^100 This strategy has already been applied for the discovery
(^93) Kim et al. (2014b), pp. 811–822; Forler et al. ( 2014 ), pp. 56–61; Vidal et al. ( 2011 ), pp. 986–998.
(^94) Drake et al. ( 2013 ), pp. E4762–E4769.
(^95) Fredolini et al. ( 2011 ), pp. 125–136.
(^96) McLerran et al. ( 2008 ), pp. 53–60; Adam et al. ( 2002 ), pp. 3609–3614.
(^97) McLerran et al. ( 2008 ), pp. 53–60; Hoffman ( 2011 ), pp. 2013–2019.
(^98) Anderson and Anderson ( 2002 ), pp. 845–867.
(^99) Breen et al. ( 2012 ), pp. S89–S100.
(^100) Mann et al. ( 2013 ), pp. 582–590.
198 D. Josic ́and U. Andjelkovic ́