Pancreatic ductal adenocarcinoma (PDAC) is usually detected late in the disease process. Clinical work-up through imaging and tissue biopsies is often complex and expensive due to a paucity of reliable biomarkers. Here, we used an advanced multiplexed plasmonic assay to analyze circulating, tumor-derived extracellular vesicles (tEV) in over 100 clinical populations. Using EV based protein marker profiling, we identified a signature of 5 markers (PDACEV signature) for PDAC detection. In our prospective cohort, the accuracy for the PDACEV signature was 84% (95% confidence interval, CI: 69–93%), but only 63–72% for single marker screening. GPC1 alone had a sensitivity of 82% (CI: 60–95%) and a specificity of 52% (CI: 30–74%) while the PDACEV signature showed a sensitivity of 86% (CI: 65–97%) and a specificity of 81% (CI: 58–95%). We show that the PDACEV signature of tEV offered higher sensitivity, specificity, and accuracy than existing serum (CA 19-9) or single tEV marker analyses. This approach should enhance the diagnosis of pancreatic cancer.

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Variability in patient responses to even the most potent and targeted therapeutics is now the primary challenge facing drug discovery and patient care, particularly in oncology and immune therapy. Variability with respect to mechanisms of induced resistance is observed both in drug-naive patients and among those who are initially responsive. Genomics has developed powerful tools for systematic interrogation of disease genotype and transcriptional states (particularly in cancer) and for correlation of these measures with parameters of disease such as histological diagnosis and outcome. In contrast, mechanistic preclinical studies remain relatively narrowly focused, leading to many apparent contradictions and poor understanding of the determinants of response. We describe the emergence of a systems pharmacology approach that is mechanistic, quantitative, probabilistic, and postgenomic and promises to do for mechanistic pharmacology what genomics is doing for correlative studies. We focus on studies in cell lines (which currently dominate mechanism-oriented analysis), but our arguments are equally valid for real tumors studied in short-term culture as xenografts and, perhaps some time in the future, in humans.