Prostate cancer (PCa) remains the most common non-skin malignancy afflicting men in the United states. It is the second leading cause of cancer-related death. The clinical diversity of PCa is dramatic, ranging from asymptomatic disease to metastatic and fatal malignancy. One cause of this clinical diversity is the remarkable intra- and inter-tumoural heterogeneity in disease genomics. As a result, currently clinically-used risk-stratification strategies do not robustly discriminate aggressive from indolent diseases, leading to systemic over- and under- treatment. Approximately 40% of men diagnosed with PCa who seek curative treatment undergo surgical removal of their prostate (radical prostatectomy, RP). Of these, approximately 30% are found at surgery to have disease outside their prostate (non-organ-confined, non-OC). These men are candidates for multi-modal adjuvant treatment with chemo- and hormone- therapy to improve outcomes. We therefore propose to tackle this problem, using fluid biomarkers to circumvent the molecular heterogeneity of the disease. Our proposal leverages an active and productive multi-investigator, multi-institutional proteomic collaboration to develop biomarkers for the early detection of locally aggressive non-organ-confined disease. Our two lead biomarkers are 1) A multiple peptide panel that discriminates OC from non-OC in EDRN phase 2 equivalent validation (Nature Communications, in press). 2) Surface expression of CUB Domain Containing Protein 1 on exosomes differentiates PCa aggressiveness (EDRN Phase 1 equivalent discovery, Oncotarget, 2016). We propose both validation of these targets in a globally-unique biobank of expressed prostatic secretions, as well as novel biomarker discovery/development strategies to extend them in the same clinical context and sample matrix. Successful completion of our proposed studies will result in validation of at least two biomarkers for clinical utility in separation of OC vs. non-OC disease, helping to personalize therapy for a tumour type that afflicts 1 in 7 North American men.

Public Health Relevance

In this grant application, we focus on detecting locally aggressive disease early enough in order to personalize treatment decisions. We have assembled an international team of experts that have worked together on this problem for almost 10 years. We plan to further validate two biomarkers that our team has developed and published recently, and we propose to discover novel additional biomarkers that may further improve decision-making and allow for greater personalization of the treatment of men with disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA214194-02
Application #
9353339
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mazurchuk, Richard V
Project Start
2016-09-15
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Eastern Virginia Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
Alfaro, Javier A; Ignatchenko, Alexandr; Ignatchenko, Vladimir et al. (2017) Detecting protein variants by mass spectrometry: a comprehensive study in cancer cell-lines. Genome Med 9:62