Background and Clinical Goals: Given the high prevalence of non-aggressive prostate cancer, the team projects focus on the early detection of cancers that are likely to progress. Investigators developed highly interactive experiments that will eventually validate biomarkers in Phases II and III in urine and in tissue samples. The 3-year projects were developed around two major independent themes: pre-validation/validation of urine-based biomarkers for early detection of clinically significant prostate cancer, and for assisting clinicians in decision making; and molecular classification and diagnosis of clinically significant prostate cancer based on tissue-discovered markers.
Project 1: Evaluation of Urine PCA3 and TMPRSS2-ERG
Study: The project will determine whether multiplex combination of urinary measurement of TMPRSS2-ERG fusion and PCA3, together with serum PSA and percent-proPSA can improve the early detection of histopathologically aggressive prostate cancer.
Project 2: Establishing Community-Based Normal Distributions of Urinary PCA3 and TMPRSS2-ERG
Study: The frequency of detection of post-DRE urinary PCA3 and TMPRSS2-ERG fusion, and percent-free PSA and percent-proPSA in serum of a community-based sample of men undergoing prostate cancer screening will be determined by this project. The goal is to examine whether frequency differs between African-American men as compared to men of other racial backgrounds, and between Hispanic-American men as compared to men of non-Hispanic ethnicity. The broad representation of many EDRN sites in this project facilitates a strong accrual of racial and ethnic minorities, thus improving the generalizability of the anticipated outcome from this work.
Project 3: Measuring Multiple Cancer Secreted Proteins
Study: Selected Reaction Monitoring (SRM) quantitative mass spectrometry (MS) will be used to identify and quantify proteins in urine. The study will discern aggressive from indolent prostate cancer by measuring multiple proteins secreted by prostate cancer cells that are shed in voided urine.
Project 4: Tissue Microarrays for Biomarker Validation
Study: Identification and testing of available tissue microarrays (TMAs) is essential for evaluation and validation of diagnostic and prognostic biomarkers. The immediate goal is to identify TMAs that are available through participating sites. A list of available TMAs is being developed which should contain statistically powered clinically defined end points, such as organ confined versus cancers with extracapsular extension; or cancers with lymph node involvement or with distant metastasis; hormone refractory cancers; neuroendocrine carcinomas. In addition, they should be accompanied by clinical data such as survival. A “Google-Document” will be developed that will allow all participants to monitor the current status of available and potentially available TMAs.
Project 5: Upgrading Gleason Scores on Radical Prostatectomies
Study: This project will determine the clinical parameters associated with upgrading Gleason scores on radical prostatectomies. The current EDRN biopsy collection protocol records significant clinical and pathology data. A subset of these individuals has undergone prostatectomy at their respective participating institutions. At the University of Michigan and Weill Cornell Medical College sites alone, there will be approximately 500 cases where patients have entered an EDRN protocol for the collection of urine and blood samples prior to surgery by the end of the second year. The major goal of this project is to ensure that all clinical parameters that can be used in conjunction with future biomarkers are assessed. This project will also include mandatory review of current literature and available data for modeling.
Project 6: Molecular Sub-Classification of ETS and Non-ETS Rearrangements
Study: This project addresses the molecular sub-classification of ETS and non-ETS rearrangements in prostate cancer. Significant data is developing to suggest that similar to the classification of acute myeloid leukemia (AML), prostate cancer can be molecularly classified to subcategories by specific genetic alterations including gene fusions and mutations. This project will try to determine the frequency of each category. This process is similar to developing a classification for AML even prior to known treatments. An immediate goal will be to identify individuals with targetable mutations. This study will use assays pioneered by EDRN investigators, which have been used in over 100 studies throughout the world and some of which are planned to be commercially available (e.g., the TMPRSS2-ERG in situ assay licensed and distributed by Ventana/Roche).
Project 7: Prostate Cancer Phenotypes and Clinical Outcomes
Study: This project is focused on prostate cancer phenotypes and clinical outcomes. Two markers, AGR2 and CD10, can group patients into three survival or disease risk categories: 1) AGR2hi/CD10lo for high survival/low risk; 2) AGR2lo/CD10hi for low survival/high risk; and 3) AGR2hi/CD10hi and AGR2lo/CD10lo for intermediate survival/risk. Additional informative sub-grouping will be provided by markers associated with Gleason pattern 4 vs. pattern 3 cells, and CD10+ vs. CD10– cancer cell types. Further reactive stroma markers will be added based on a recently developed classification.
Project 8: Vascular Tissue Biomarkers for Molecular Imaging
Study: This project centers on the identification of cancer related vascular tissue biomarkers for molecular imaging. This project directly addresses a need to develop molecular biomarkers that can identify tumor endothelium. Validated biomarkers will then be handed off for further development by the Stanford BDL group. These biomarkers will enhance the group’s ability to monitor cancers over time and seek associations with biomarkers developed by other team projects of this collaborative group. A specific example might be a particular vascular pattern seen in ERG-rearranged prostate cancers as compared to non-rearranged cancers given the important role of ERG in vascular development.
Other EDRN News: Urine Test Added to PSA May Indicate Increased Risk for Prostate Cancer
Researchers from NCI’s Early Detection Research Network have published findings on a urine test that may be used to better determine which men with elevated PSA readings are at highest risk for invasive prostate cancer. Read more at the University of Michigan website at:
The paper, titled, Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA, was published in the August 3, 2011 issue of Science Translational Medicine .