Challenges and Opportunities in Clinical Applications of Blood-Based Proteomics in Cancer

Simple Summary The traditional approach in identifying cancer related protein biomarkers has focused on evaluation of a single peptide/protein in tissue or circulation. At best, this approach has had limited success for clinical applications, since multiple pathological tumor pathways may be involved during initiation or progression of cancer which diminishes the significance of a single candidate protein/peptide. Emerging sensitive proteomic based technologies like liquid chromatography mass spectrometry (LC-MS)-based quantitative proteomics can provide a platform for evaluating serial serum or plasma samples to interrogate secreted products of tumor-host interactions, thereby revealing a more complete repertoire of biological variables encompassing heterogeneous tumor biology. However, several challenges need to be met for successful application of serum/plasma based proteomics. These include uniform pre-analyte processing of specimens, sensitive and specific proteomic analytical platforms and adequate attention to study design during discovery phase followed by validation of discovery-level signatures for prognostic, predictive, and diagnostic cancer biomarker applications. Blood is a readily accessible biofluid containing a plethora of important proteins, nucleic acids, and metabolites that can be used as clinical diagnostic tools in diseases, including cancer. Like the on-going efforts for cancer biomarker discovery using the liquid biopsy detection of circulating cell-free and cell-based tumor nucleic acids, the circulatory proteome has been underexplored for clinical cancer biomarker applications. A comprehensive proteome analysis of human serum/plasma with high-quality data and compelling interpretation can potentially provide opportunities for understanding disease mechanisms, although several challenges will have to be met. Serum/plasma proteome biomarkers are present in very low abundance, and there is high complexity involved due to the heterogeneity of cancers, for which there is a compelling need to develop sensitive and specific proteomic technologies and analytical platforms. To date, liquid chromatography mass spectrometry (LC-MS)-based quantitative proteomics has been a dominant analytical workflow to discover new potential cancer biomarkers in serum/plasma. This review will summarize the opportunities of serum proteomics for clinical applications; the challenges in the discovery of novel biomarkers in serum/plasma; and current proteomic strategies in cancer research for the application of serum/plasma proteomics for clinical prognostic, predictive, and diagnostic applications, as well as for monitoring minimal residual disease after treatments. We will highlight some of the recent advances in MS-based proteomics technologies with appropriate sample collection, processing uniformity, study design, and data analysis, focusing on how these integrated workflows can identify novel potential cancer biomarkers for clinical applications.