MTOPS Prostate Samples Analysis (MPSA) Consortium

• Background: BPH
• Medical Therapy of Prostatic Symptoms (MTOPS) Study
• MPSA Study

Background: Benign Prostatic Hyperplasia

Benign Prostatic Hyperplasia (BPH) affects more than 50 percent of men past the age of 50. It is an expensive disease, with treatments costing an estimated $5 billion a year, and those costs are expected to increase as the U.S. male population ages. If left untreated, BPH can lead to urinary tract infections, urinary retention, and, in occasional cases, kidney disease. BPH is a heterogeneous disorder, with growth occurring at variable rates in different portions of the gland and a variable clinical presentation and response to therapy. Although BPH and prostate cancer have not been clearly linked, these two prostate diseases occur in a similar population of aging men.

However, unlike prostate cancer, BPH does not have a screening tool. BPH must be diagnosed clinically by symptoms, physical exam, and diagnostic imaging. Better markers for BPH are needed as well as genetic tests to identify patients at high risk for early BPH, for rapidly progressing BPH, and for prostate cancer. Genetic tests are also needed to determine which patients will respond to various forms of pharmacological therapy. Examination of the large number of well-characterized patients in the MTOPS trial should allow for the development and testing of such markers.

The MTOPS Interventional Study

A large clinical trial called Medical Therapy of Prostatic Symptoms or MTOPS investigated two drug treatments for benign prostatic hyperplasia (BPH)-finasteride and doxazosin. The study found that a combination of the two drugs is significantly more effective than either drug alone for preventing progression of benign prostatic hyperplasia (BPH), especially in men at high risk for disease progression [DKwebmaster: link to http://www.niddk.nih.gov/welcome/releases/12-17-03.htm].

• Serum samples from 4,000 patients
• Tissue samples from approximately 900 patients who had prostate biopsies.

Serum samples were collected at the beginning of the study and at yearly intervals. Approximately one-quarter of the participants had prostate biopsies taken at years 0, 1, and 5. The serum and prostate biopsy samples are stored currently in a repository at the MTOPS Pathology Coordinating Unit.

Clinical information for each patient is stored in the MTOPS Data Coordinating Center. The pathological diagnoses of tissue biopsy samples are predominantly chronic prostatitis, simple atrophy, or the various forms of hyperplasia (e.g., adenomatous, fibromyoadenomatous, and leiomyoma). Their availability presents an extraordinary opportunity to develop and evaluate biological and genetic markers that will further our understanding of the processes that contribute to BPH and prostate cancer or that are related to response to therapy of BPH. The importance of prostate biomarkers has been repeatedly emphasized at national and international meetings.

The MPSA Consortium

The MPSA Consortium, established in 2002 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), is a cross-disciplinary, multi-institutional network with a wide range of experts. Participating in the MPSA network are one pathology-coordination center, six biomarker units, and a data coordinating center. The consortium comprises UT Southwestern, Vanderbilt University, Brigham and Women's Hospital, Harvard/University of Michigan, Baylor College of Medicine, University of Pittsburgh, and University of Colorado.

The MTOPS Prostate Samples Analysis (MPSA) Consortium will analyze serum and tissue samples collected in the MTOPS trial. The consortium aims to discover and validate biomarkers for the detection, risk assessment, and disease progression assessment of BPH. Analysis of the samples will also allow a biological evaluation of patients' responses to pharmacological treatments employed in MTOPS and correlation with BPH clinical parameters. Investigators will perform cooperative studies using the MTOPS material to evaluate genetic, immunologic, or biochemical biomarkers relevant to the progression of BPH, response-to-therapy, and the concurrent development of prostate cancer. The consortium will generate and validate biomarkers that will be made available to research community for use in a variety of investigations, including testing strategies for early detection, prevention, therapeutics, or imaging. The consortium will also produce research tools such as serum protein arrays, layered expression arrays, or tissue arrays that can be used by the research community.

To identify novel targets for use as validated BPH markers, the consortium is currently exploring novel aspects of BPH biology and response to therapy. Several groups are using proteomic approaches, including SELDI, other types of mass spectrometry analysis, and 2D electrophoresis. Other groups are pursuing gene expression microarray analysis.

The consortium is also organizing available data to identify current gaps. Groups with additional microarray data that has focused on BPH have compiled a common database of genes with expression patterns that are altered with the disease. This combined dataset will be used to identify some novel biomarkers revealed by single-site analyses. These novel biomarkers will then be validated using the tissues and serum microarrays that are being assembled. Another collaborative effort of the consortium involves construction of common tissue and serum resources and tissue microarrays (TMAs). Lists of available resources at each of the consortium member sites have been assembled along with information addressing secondary outcomes such as prediction of prostate growth and prediction of disease progression. Initial tissue microarrays composed of tissues from a number of sites have been constructed. Additional TMAs and serum microarrays are being constructed; these microarrays will be used by consortium members to aid in the validation of potential biomarkers.

Project Officers: Chris Mullins, Ph.D., 301-594-7717; Robert Star, M.D., Ph.D., 301-594-7717