Urinary Protein Biomarker Analysis
Abstract
In prostate cancer disease management, overdiagnosis and overtreatment have increasingly become major public concerns. Prostate cancer is primarily detected by serum PSA (prostate-specific antigen) screening followed by a transrectal ultrasound-guided biopsy for those with abnormal PSA. However, a majority of those biopsied have no cancer (overdiagnosis). Furthermore, many cancer patients would undergo aggressive therapy for tumors with low malignant potential (low risk, overtreatment). Therefore, the need for better noninvasive biomarker testing is urgent for specific detection of high-risk cancer and for monitoring tumor progression for low-risk patients under active surveillance so that the number of invasive biopsies can be greatly reduced. The objective is, therefore, to develop a so-called "liquid biopsy" based on a protein-based multi-marker urine test that is equivalent or better than a physical biopsy for cancer detection and risk stratification. We believe that a multi-marker test will be the most promising to counter the heterogeneous nature of the disease, where single markers cannot. A multi-marker urine test is highly attractive because prostate cancer cells and cancer-associated proteins are released into the urine. The past challenge for the development of multi-marker tests is the lack of sensitive technologies to measure multiple analytes and the lack of ability to distinguish specific protein isoforms. We have developed uniquely highly sensitive mass spectrometry technologies to enable multiplexed quantification of cancer-associated secreted proteins and protein isoforms that exist at very low concentrations in urine (as expected of cancer biomarkers). The multiplexed and isoform-specific quantification of secreted protein products in urine is particularly innovative because this cannot be achieved by traditional immunoassays. Our integrative strategy starting from cancer cell type-specific transcriptome profiling to highly sensitive multiplexed quantification of secreted protein products in urine provides a highly promising approach for identifying multi-marker panels for the detection of high-risk prostate cancer, and for the eventual development of a multi-marker urine test for disease stratification in the clinic. Our data provided strong support for the feasibility of multi-markers to distinguish high-grade tumors from low-grade tumors. We focus on urine testing because urine collection represents the least invasive route of obtaining biomaterial. Being a natural waste product, multiple samples can be conveniently taken without risk or stress to the patients. The collection is simple at patients convenience. We anticipate that it may take about 5 years to successfully introduce a clinically useful test. The outcome will be the first non-invasive multi-marker clinical urine test for detection of high-risk prostate cancer. The clinical utility of a urine test would be to reduce the number of unnecessary biopsies (or all biopsies) because the information gained from multiple markers -- cancer-associated secreted proteins -- would provide the means to distinguish the few high-risk cases from the majority of low-risk cases. For patients undergoing active surveillance for low-risk disease, the urine test can be used to monitor changes in biomarker signals indicative of progression instead of repeat biopsies. Biopsy has a significant chance of missing important small high-grade tumor foci. Such undersampling is avoided with urine testing as all parts of the prostate "drain" into the urine. Moreover, multiple marker testing may dramatically change the paradigm of current medical practice for prostate cancer. For example, the protein signatures can be used for screening. For every man, a non-cancer/healthy urine signature will be determined. Changes in this signature would indicate the presence of diseased tissue including prostate cancer along the urinary tract. Prostate cancer
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610614
Entities
People
- Alvin Liu
Organizations
- United States Army
- University of Washington