The Role of Proteomics in Biomarker Development for Improved Patient Diagnosis and Clinical Decision Making in Prostate Cancer

Abstract

Prostate Cancer (PCa) is the second most commonly diagnosed cancer in men worldwide. Although increased expression of prostate-specific antigen (PSA) is an effective indicator for the recurrence of PCa, its intended use as a screening marker for PCa is of considerable controversy. Recent research efforts in the field of PCa biomarkers have focused on the identification of tissue and fluid-based biomarkers that would be better able to stratify those individuals diagnosed with PCa who (i) might best receive no treatment (active surveillance of the disease); (ii) would benefit from existing treatments; or (iii) those who are likely to succumb to disease recurrence and/or have aggressive disease. The growing demand for better prostate cancer biomarkers has coincided with the development of improved discovery and evaluation technologies for multiplexed measurement of proteins in bio-fluids and tissues. This review aims to (i) provide an overview of these technologies as well as describe some of the candidate PCa protein biomarkers that have been discovered using them; (ii) address some of the general limitations in the clinical evaluation and validation of protein biomarkers; and (iii) make recommendations for strategies that could be adopted to improve the successful development of protein biomarkers to deliver improvements in personalized PCa patient decision making.

Keywords: biomarkers; clinical validation; multiple reaction monitoring; prostate cancer; proteomics.

Figure 1

PSA screening and over diagnosis: The info graphic indicates the proportion of patients for which a true diagnosis versus of prostate cancer is achieved as result of PSA screening (a); A common reason for misdiagnosis is that a similar trajectory of PSA increase is often observed in men who have benign prostatic hyperplasia (BPH) (b). Figure adapted from Lin, K et al. and Roobol, M., et al. (2012) [30,31].

Figure 2

PubMed Search Results for Proteomics and Prostate Cancer: A PubMed search was conducted in March 2016 with the search terms “Prostate Cancer” AND “Proteomics”. The total number of ‘hits’ was 533, with dramatic increases observed for the years 2003 and 2013.

Figure 3

Dynamic range of protein concentrations in biological fluids: Figure 3 gives a breakdown of the concentration of proteins found in blood (A) and urine (B) samples. Notably, blood proteins, which are considered to be significant to biomarker discovery studies, make up less than 10% of the total concentration of blood proteins [167,170].

Figure 4

Proteomic Technology for Discovery and Evaluation of Protein Biomarkers.

Figure 5

Discovery and Clinical Implementation of Protein Biomarkers: outline of the process involved in bringing candidate protein biomarkers through from the discovery phase, evaluation and ultimately to adoption as a clinical assay for subsequent validation (Figure adapted from Rifai et al., 2006 [116].

Figure 6

Longitudinal Evaluation of Candidate Prostate Cancer Biomarkers in Patient Serum Samples: Serum samples collected from patients who had failed treatment with CHRT (n = 3) and time-matched controls still responsive to CHRT (n = 3) (A) were used to longitudinally evaluate the expression of multiple markers of PCa, including PSA (B) and zinc-slpha-2-glycoprotein (C) via MRM measurement of proteotypic peptides. Figure adapted from Tonry et al. 2015 [247].