Biomarkers to stratify pain severity and type in pancreatic disease

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PROJECT SUMMARY Chronic pancreatitis (CP) results from progressive inflammation and fibrosis, most commonly from acute pancreatitis (AP) and recurrent episodes of AP (RAP), and is associated with long term complications of diabetes and exocrine pancreatic insufficiency. Pain is one of three diagnostic criteria for AP and multiple studies have now confirmed that pain is also the most significant symptom for patients with CP (77-93%). While there are a variety of interventions available to treat pain, many of which are not efficacious in CP patient: only ~25% chronic pancreatitis patients achieve meaningful pain relief with current standard of care for pain management. As of now, there are no chronic pancreatitis pain biomarkers to stratify pain based on severity and/or type, which would guide physician decision making or monitor therapeutic responses. This contributes to the immense burden of pain in this CP patient population. To address this gap in knowledge, we will leverage the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) which has been realized under the auspice of the NIDDK-/ NCI-funded Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC). PROCEED, which will be a key resource for this proposal, is the first prospective longitudinal CP cohort in the U.S. It has enrolled 1638 (and counting) participants with CP, AP, and RAP, as well as healthy and non- pancreatitis symptomatic controls. All participants of this unique cohort undergo deep phenotyping, provide detailed information on clinical symptoms, and general QoL variables. Furthermore, 10 pain-associated variables are recorded providing detailed information about pain types, severities and interventions. Due to the size and multi-site nature of PROCEED, the cohort was split into independent discovery and validation cohorts to enable FDA-compliant biomarker validation. In Specific Aims 1 and 2 of this proposal, we will use plasma and urine samples from the PROCEED discovery cohort (n >500) to generate quantitative multi-omics datasets of the proteins, chemokines, cytokines and neuropeptides. Mass spectrometry-based discovery proteomics and multiplexed antibody-based assays will be used for the biomarker identification. Upon discovery of promising pain biomarkers, we will transition to the validation phase (Specific Aims 3 and 4). In this phase, we will use the urine and plasma samples from the independent PROCEED validation cohort (n >500) to validate the potential biomarkers identified in the Specific Aims 1 and 2. We will use targeted liquid chromatography/mass spectrometry methods as well as antibody-based method for the validation. The large number of PROCEED samples and their superb annotation will allow for an exquisitely granular pain-focused analysis of the resulting large scale proteomic and cytokine/chemokine assay data.