A road map to biomarker discovery and validation in urological chronic pelvic pain syndrome.

Biomarkers and surrogate end points are important tools in the diagnostic and therapeutic armamentarium. By definition a biomarker is a biological characteristic that is measured and evaluated objectively as an indicator of normal biological or pathogenic processes (a diagnostic biomarker), or a pharmacological response to therapeutic intervention (a therapeutic biomarker).1 Thus, any patient parameter that can be measured, for example, mRNA expression profiles, proteomic signatures, protein or lipid levels, imaging methods or electrical signals, may serve as a biomarker. The best biomarkers are accurate, relatively noninvasive and easy to perform tests that can be done at the bedside or in the outpatient setting. In contrast, a surrogate end point marker is the rare biomarker that can substitute (or be a surrogate) for a clinical end point such as survival, stroke, fracture or cancer recurrence.1 CD4 counts are typically used as surrogate end point markers in the treatment of patients with HIV. Hewitt et al recently described 11 steps in the development and validation of urinary, serum and tissue biomarkers.2 Two articles in this issue of The Journal provide a road map to biomarker discovery and validation in chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/painful bladder syndrome (IC/PBS). Expanding on their previous findings in a well characterized patient cohort, Desireddi et al (page 000) reported on 2 candidate diagnostic biomarkers for CP/CPPS, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). ROC analysis incorporating expressed prostatic secretion (EPS) MCP-1 levels greater than 704 pg/ml and MIP-1α levels greater than 146 pg/ml correctly distinguished patients with CP/CPPS from controls with an accuracy of 90%. In addition, MIP-1α levels strongly correlated with the pain domain subscore of the National Institutes of Health-Chronic Prostatitis Symptom Index (p=0.0007). On the other hand Erickson et al (page 000) found a positive association between urinary interleukin (IL)-8 levels and bladder mast cell counts, but did not observe a robust association among urinary IL-6, cyclic guanosine monophosphate, heparin-binding epidermal growth factor-like growth factor, epidermal growth factor, antiproliferative factor and bladder biopsy findings in patients with or without ulcer. As noted by Hewitt et al the road to biomarker discovery starts with understanding and defining the disease.2 However, the symptoms of IC/PBS and CP/CPPS significantly overlap with other common conditions, and are not associated with any pathognomonic changes. In this respect the main issue in diagnosing CP/CPPS and IC/PBS appears to be the fact that researchers have traditionally attempted to define those conditions as “categorical” entitites, that is, as states that can be qualitatively separated from the state of being “well”. However, it is well-known by practicing clinicians that CP/CPPS and IC/PBS might be better conceptualized as “dimensional” conditions. Similar to the situation in neuroscience, dimensional or quantitative traits are considered to be continuous with the “normal” state and at the gene level are consistent with the polygenic mode of inheritance. In this respect the articles by Desireddi and Erickson et al provide the guiding signs on the road map for CP/CPPS and IC/PBS biomarker discovery. MCP-1 and MIP-1α levels in EPS and urinary IL-8 can be used as potential therapeutic biomarkers to select a potential, well characterized patient population for targeted therapeutic intervention. In addition, they can provide good therapeutic biomarker based end points in future clinical trials on CP/CPPS and IC/PBS. The implications of these 2 studies actually go well beyond the clinical application of the biomarkers. Mechanistically Desireddi et al implicated the prostate in the pathogenesis of CP/CPPS symptoms, and Erickson et al describe an association of IL-8 and mast cells in bladder biopsies. It is a well-known fact in clinical practice that while patients often present with end organ (bladder or prostate) disease, a significant number of them also have systemic symptoms, eg fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, etc. In this respect the biomarkers described in the 2 articles can also be used to define a population that can perhaps benefit from end organ interventions, eg intraprostatic injections or bladder instillation. Several recent lines of evidence suggest that CP/CPPS and IC/PBS result from different environmental triggers in a genetically susceptible individual (see figure).3–5 Emerging evidence from twin and family based studies of CP/CPPS and IC/PBS suggests that what we now consider a single disorder might actually result from the interaction of a large number of common genetic variants, with no variant proving necessary or sufficient for the condition to develop. Alternatively, similar to the situation in depression and anxiety, CP/CPPS and IC/PBS might actually result from diverse individual mutations and, thus, represent a large family of rare Mendelian diseases with a similar pathophysiology, as has been shown to be the case with retinitis pigmentosa.6 A third and more recent hypothesis for the pathogenesis of IC/PBS and CP/CPPS is that they might result from new germline mutations that act against certain genetic backgrounds as suggested for some cases of autism and schizophrenia.7 The value of examining those possibilities is that defining a genetic biomarker for IC/PBS and CP/CPPS can provide important insights into the validation of other protein based biomarker assays, as well as provide the mechanistic basis for therapeutic clinical trials. Figure Significance of urinary and EPS biomarkers in context of CPPS mechanisms. CCL, cysteine-cysteine ligand. GAG, glycosaminoglycan. Asterisk indicates Erickson et al. Dagger indicates Desireddi et al. In this respect IC/PBS and CP/CPPS are best conceptualized as a spectrum of clinical phenomena in a genetically susceptible individual. An environmental trigger provides the “second hit,” and sets the stage for an abnormal and inadequately controlled inflammatory response with subsequent inflammatory mediator release as shown in the 2 studies (see figure). Subsequent changes in bladder and prostatic tissue chemical milieu result in downstream molecular and cellular events which eventually culminate in the symptoms of CP/CPPS and IC/PBS. Future clinical studies, ideally using high-throughput genomic and proteomic approaches, should define the exact molecular and cellular events that are involved in those clinical phenomena. Such studies should provide information on hundreds and thousands of genes and proteins that mediate the link between the observed cytokine and chemokine levels, and the clinical phenomena of pain and voiding symptoms that are characteristic of CP/CPPS and IC/PBS.