SPOREs : Organ-Specific SPORE Programs : Prostate

Project 1
Osteoclastogenesis as a Target for Prostate Cancer Osseous Metastases Therapy
Principal Investigator: Evan Keller, DVM, PhD
Co-Principal Investigator: David Smith, MD

Prostate cancer skeletal metastases are considered osteoblastic; however, histopathological examination usually reveals underlying osteoclastic activity. A key molecule required for induction of osteoclastic activity is receptor activator of NFkB ligand (RANKL). We have determined that prostate cancer cells express increasing levels of RANKL and induce osteoclastogenesis as they progress to bone metastases. Furthermore, in a murine model, we have demonstrated the ability to inhibit establishment of prostate cancer in bone by blocking RANKL-induced osteoclastic activity. Thus, our hypothesis is that RANKL contributes to the development of prostate cancer skeletal metastases, which we will test in the following specific aims:

Aim 1. Identify the mechanisms through which RANKL expression is regulated in prostate cancer cells. To understand why RANKL mRNA expression is increased in prostate cancer skeletal metastases, we will characterize the RANKL gene promoter in vitro and in vivo and determine cis-acting sites and trans-acting factors that induce RANKL expression in skeletal metastases.

Aim 2. Determine if RANKL is required for the establishment and progression of prostate cancer skeletal metastases in vivo. We will inject prostate cancer tumors into human bone implanted in SCID mice and administer inhibitors of RANKL (i.e., soluble RANK or anti-RANKL antibody) at the time of tumor injection or after tumors become established. We will determine establishment/progression of tumors and expression of bone remodeling markers in the mice.

Aim 3. Investigate the effect of docetaxel and estramustine (DE), and a bisphosphonate (Zometa®) (Z) on systemic markers of bone remodeling and RANKL expression in bone metastases in men with prostate cancer bone metastases. Men with scan positive bone metastases will be treated with one cycle of Z or DE. This will be followed by two additional cycles of ZED together. Bone markers and indices of prostate cancer response/progression (PSA/bone scans) will be measured at various timepoints. Pre- and post-treatment biopsies of bone metastases in selected patients will be evaluated for RANKL and OPG protein expression.

Project 2
The Role of Protease Activated Receptor-1 in Prostate Cancer Metastasis
Principal Investigator: Kenneth J. Pienta, MD
Co-Principal Investigator: David P. Wood, MD
Co-Investigator: Alvin Schmaier, MD

The hypothesis of this application is that activation of PAR1 is a critical step in prostate cancer tumorigenesis and inhibition of this step can lead to an effective treatment for prostate cancer. Effective treatment of prostate cancer will come from understanding the biology of this disease and applying this knowledge to the application of specific therapies. The development of new interventions for this disorder requires identification of specific targets to attack in men with prostate cancer.

There are three major problems in attempting to treat prostate cancer. The first is the establishment of relevant models to test therapeutic agents in the pre-clinical setting before moving agents to the clinical setting. The second is the identification of therapeutic agents for intervention. The third problem is the optimal design of clinical trials that adequately test the agents identified in the pre-clinical setting. In the previous grant period, we have established in vitro and in vivo models of prostate cancer and used these models to identify potential targets and agents for intervention. This application focuses on PAR1 (protease activated receptor 1, the thrombin receptor) as a new target for therapeutic intervention in prostate tumorigenesis. In our preliminary data / progress report, we demonstrate PAR1 is overexpressed on prostate cancer cells as compared to normal prostate tissue by cDNA and tissue microarray. The Specific Aims of this proposal are as follows:

Specific Aim 1: Characterize the functional role of the thrombin receptor (protease activated receptor 1, PAR1) in prostate cancer metastasis. We have identified that PAR1 is differentially expressed in prostate cancer cells and tissue compared to normal prostate. We will investigate the effects of blocking PAR1 in high-expressing VCaP cells and over expression of PAR1 in low-expressing DU145 cells in adhesion, motility, and invasion assays.

Specific Aim 2: Test whether inhibitors of PAR1 prevent prostate cancer metastasis in preclinical models in vivo and establish benchmarks by which specific thrombin inhibitors will be chosen for future clinical trials in prostate cancer metastasis prevention and treatment. We will use in vivo model systems to test whether inhibitors of PAR1 decrease prostate cancer metastasis, growth and proliferation.

Specific Aim 3: We will characterize the quantity and PAR1 phenotype of circulating prostate cancer cells in patients with hormone refractory prostate cancer to establish the basis for future clinical trials to examine PAR1 inhibitors for prostate cancer metastasis prevention and treatment. Levels of circulating cells will be measured in patients with metastatic prostate cancer, eventually prior to and after thrombin inhibitor administration if deemed to be appropriate.

These proposed studies will characterize the role of PAR1 in prostate tumorigenesis and begin to define therapeutic strategies to treat prostate cancer by inhibition of PAR1 activation.

Based on Dr. Pienta's discovery that inhibitors of PAR1 did not inhibit metastasis in vivo in preclinical models which eliminated the translational potential of this project, the Clinical Applications Committee and Operating Committee elected to terminate this project in May 2005.

Project 3
Signature Lethal Biomarkers of Prostate Cancer
Principal Investigator: Arul M. Chinnaiyan, MD, PhD
Co-Principal Investigator: James E. Montie, MD
Co-Investigator: Mark A. Rubin, MD; Martin G. Sanda, MD

Afflicting one out of 9 men over age 65, prostate cancer (PCA) is a leading cause of male cancer-related death, second only to lung cancer. The American Cancer Society estimates that 198,100 American men will be diagnosed with PCA and 31,500 will die this year .While effective surgical and radiation treatments exist for clinically localized PCA, metastatic PCA remains essentially, incurable and most men diagnosed with metastatic disease will succumb over a period of months to years. The molecular differences between metastatic prostate cancer and localized prostate cancer are not well established. Before prognostic markers and rational therapies can be developed to target this lethal form of prostate cancer, the molecular alterations associated with it need to be unmasked. Our overall hypothesis is that metastatic (advanced) prostate cancer expresses genes that can be used to predict the aggressive potential of clinically localized prostate cancer. These "signature" lethal genes have potential as prognostic biomarkers, therapeutic targets, and may play a role in the progression from localized disease. The advent of high-throughput genomic and proteomic techniques raises new hopes for identifying novel molecular targets for therapy. In this proposal, we will implement novel bioinformatic approaches to identify candidate lethal biomarkers from the gene expression profiles of metastatic prostate cancer (Aim 1 ). These lethal genes will be evaluated on clinically stratified prostate cancer tissue microarrays (Aim 2). The most promising candidates will be tested in a cohort of prostate needle biopsies for their ability to predict clinical aggressiveness (Aim 3). By pursuing these studies we hope to identify a set of lethal biomarkers that will be useful for guiding treatment decisions for individual patients and that may also have potential as therapeutic targets.

Project 4
Defining Genetic Risk Factors for Brothers of Men with Prostate Cancer
Principal Investigator: Kathleen A. Cooney, MD
Co-Principal Investigator: David P. Wood, MD
Co-Investigator: Stephen Gruber, MD, PhD

Men with a family history of prostate cancer have a two to four-fold excess risk of developing prostate cancer compared to those with no family history. The degree of risk elevation associated with familial prostate cancer may depend on several factors including the age at diagnosis of the affected family members and the total number of affected first and/or second-degree relatives. Many multiplex prostate cancer families have been studied over the last decade with the goal of identifying highly penetrant prostate cancer genes using linkage approaches, however, many of these prostate cancer genes remain elusive. An alternative strategy for the identification of prostate cancer susceptibility genes is the use of association studies, which have generally used case:control datasets to study low penetrance genes. The University of Michigan Prostate Cancer Genetics Project (PCGP) is a family-based study with the goal of characterizing the molecular basis for the inherited predisposition to prostate cancer. We hypothesize that prostate cancer susceptibility loci with modest penetrance can also be identified and characterized using family-based association studies. Since prostate cancer is a late-onset disease, and parental genotype information from parents is typically unavailable, we will focus primarily on understanding the genetic differences between men with prostate cancer and their unaffected male siblings. Therefore, to characterize prostate cancer susceptibility genes using prostate cancer families, the following three Specific Aims are proposed:

1. To ascertain, characterize, and classify sibling pairs discordant for prostate cancer from the University of Michigan Prostate Cancer Genetics Project (PCGP).
2. To identify one or more genes that associate with the generalized risk of prostate cancer among discordant sibling pairs (DSPs) from the PCGP.
   1. To characterize genes that associate with the diagnosis of early-onset and/or hereditary prostate cancer among the DSPs.
   2. To study genes that associate with the development of clinically advanced prostate cancer (i.e., high stage and/or high grade) among the DSPs.

The translational goal of our project is to identify genes that can be used to determine risk of prostate cancer as well as clinically aggressive prostate cancer in unaffected men with a family history of prostate cancer.

Project 5
Multiple Mechanisms of Androgen Resistance in Prostate Cancer Progression
Principal Investigator: Diane M. Robins, PhD
Co-Principal Investigator: Kenneth J. Pienta, MD

Prostate cancer initially depends on androgens for growth and initially responds to androgen ablation therapy. Nevertheless, the cancer ultimately becomes resistant to anti-androgens and disease progression occurs. However, the tumors retain androgen receptor (AR) and its downstream signaling pathway. Resistance may be due to several factors. First, anti-androgens may display partial agonist behavior, the basis of which may vary with the compound. Second, mutant ARs may arise during treatment, with reduced ligand specificity or ligand-independent activity. These mutant ARs may show differential resistance to particular antagonists. An overall hypothesis of this proposal is that mutant ARs are selected during treatment of prostate cancer with anti-androgens and allow progression of androgen-independent disease. Our specific hypotheses are that: 1) The commonly used antagonists, bicalutamide and flutamide, differ in their precise mechanism of action, and thus mutant ARs resistant to one may not have a similar advantage against the other. 2) Partial agonism may in some cases be due to interactions of hormone- and antagonist-bound receptors. This suggests that disease progression may vary dependent on antagonist. Understanding mechanisms of androgen resistance, and if it varies with antagonist, may lead to improved treatment regimens and novel targets for therapy.

Aim I. To determine the molecular basis for differential partial agonism of bicalutamide vs. flutamide. We will assess interaction of antagonist-bound ARs with nonreceptor proteins, and interaction of agonist- and antagonist-bound ARs in mixed ligand dimers. This will be analyzed biochemically using in vitro assays, including co-precipitation with glutathione-S-transferase-fused proteins, and functionally in transfected cells, for wild type AR and mutant forms found in prostate cancer.

Aim II. To test whether prostate cancer growth and progression is delayed by sequential or combined antagonists, and whether this correlates with AR variation, in three complementary mouse models of prostate cancer. This Aim will utilize two new, prostate cancer mouse models: the VCaP xenograft model of hormone-sensitive (but not dependent) prostate cancer derived from a participant in the SPORE warm autopsy program, and the h/mAR TRAMP model of humaized AR in the TRAMP background. VCaP and h/mAR TRAMP mice will be randomized to groups treated with bicalutamide, flutamide, both or neither. Tumor growth between treament arms will be compared and AR cDNAs will be scanned for mutations. Mutations will be tested for functional effect on AR in vitro.

Aim III. To determine whether antiandrogen treatment differentially affects human disease progression and correlates with distinct AR mutations. AR sequences will be determined in samples from the rapid autopsy program, for patients treated with flutamide vs. bicalutamide, in comparison to hormone-naïve Ulm patient samples. Mutations will be compared to those in mice, and any novel mutations will be introduced into vectors to test the functional effect on AR in vitro.

Project 6
Evaluation and Development of Non-Peptide Small-Molecule MDM2 Inhibitors as a New Therapy for Advanced Prostate Cancer
Principal Investigator: Shaomeng Wang, PhD
Co-Principal Investigator: Kenneth J. Pienta, MD
Co-Investigator: Rajal Shah, MD

After Project 2 was terminated, this project was chosen by competition as a replacement. This project began 6/1/05.

Our major objectives in this proposal are to evaluate the therapeutic potential of potent, non-peptide, drug-like, water-soluble small-molecule inhibitors of MDM2 which we have recently designed and synthesized as a new therapy for the treatment of advanced prostate cancer; and to elucidate their molecular mechanism of action in prostate cancer models. Sccessfully carriedout, this project will lead to the development of an entirely new class of molecularly targeted anti-cancer therapy for the treatment of advanced prostate cancer by stimulating the activity of p53 through blocking the p53-MDM2 interaction.

Aim 1: (a) In vitro evaluation of 8-10 potent, non-peptide small-molecule MDM2 inhibitors for their anticancer activity in human prostate cancer cells, alone and in combination with chemotherapeutic drugs; and (b) elucidation of their molecular mechanism of action in prostate cancer cells.

Aim 2: Determination of the therapeutic potential of the 3-5 most promising MDM2 inhibitors in animal models of human prostate cancer, alone and in combination with current chemotherapeutic agents.

Aim 3: (a) Analysis of MDM2 and related proteins of prostate cancer tissue microarrays and correlations with measures of clinical outcome; and (b) isolation of cells from the circulation of patients with androgen-independent prostate cancer and determination of p53 status of circulating cancer cells.

Core 1
Administrative Core
Principal Investigator(s): Kenneth Pienta, M.D.
Co-Principal Investigator(s): Kathleen A. Cooney, MD; James E. Montie, MD

The University of Michigan Comprehensive Cancer Center (UMCCC) Prostate SPORE administrative core is responsible for leadership, guidance and management. The administrative core oversees all aspects and performs numerous duties across the expansive scope of the SPORE. These duties are: 1) provide scientific leadership to the SPORE investigators; 2) direct the translational components of the overall SPORE program; 3) function as the coordinating unit for SPORE activities and information; 4) oversee and administer all budgetary issues and finances; 5) maintain UMCCC Prostate SPORE web page; 6) provide administrative framework for all projects, research development, career development, and cores; 7) administer the yearly competition for pilot projects and seed grants; 8) apply cost effectiveness and quality control factors; 9) facilitate interactions between the SPORE and the University, 10) facilitate interactions between the SPORE and other SPOREs and the NCI; 11) communicate with NCI program staff and coordinate submission of required reports; 12) convene and provide administrative support for meetings; 13) provide oversight for the recruitment of women and minorities; 14) assure compliance with regulations regarding animals in research; 15) coordinate quality assurance between tissue banks and databases; and 16) coordinate and organize community outreach efforts. Kenneth J. Pienta, MD, director of urologic oncology for the University of Michigan Comprehensive Cancer Center continues to serve as principal investigator of the Administrative Core. Kathleen Cooney, MD, serves as the co-principal investigator of the Administrative Core. Dr. Cooney oversees all of the developmental programs as well as the Biostatistics and Tissue Cores. James Montie, M.D., serves as a co-principal investigator responsible for the translational science of the SPORE and directs the new Clinical Applications Core. Ms. Jill Miller has filled the role as SPORE administrator since 1998 and will continue in this role. She has demonstrated her ability to administer this large research program in an efficient manner. This core provides the framework to support the success and mission of the UMCCC SPORE as a cohesive group of investigators committed to the development of translational research in prostate cancer.

Core 2
Biostatistics Core
Principal Investigator(s): Jeremy Taylor, PhD

The goal of the Biostatistics Core is to collaborate with SPORE investigators and other core resource scientists to enhance the quality of the research undertaken in the University of Michigan Prostate SPORE. The Core personnel have been chosen because of their expertise in relevant areas of Biostatistics and because of their experience and knowledge of prostate cancer.

Biostatistics Core personnel will collaborate with every one of the six proposed projects, will interact with the other cores and also will expect to interact with all funded development awards, and thus this core is crucially important to the SPORE. Personnel from the core will interact with the investigators in all stages of the research, beginning with the formulation of the research question, through the experimental design stage and data collection stage, to data analysis and interpretation, to the writing of reports and dissemination of results. Two areas where biostatistical expertise is indispensable are in experimental design and data analysis. It will be apparent from this proposal that Core personnel have played a significant role in designing the proposed experiments and in planning the data analysis. The Specific Aims of the Core are 1) assist investigators in the design of clinical and laboratory experiments; 2) assist investigators in the analysis and interpretation of data from clinical and laboratory experiments and in writing of scientific manuscripts relaying prostate cancer SPORE results to the scientific community; and 3) undertake translational biostatistics research to develop methodology relevant to prostate cancer.

Core 3
Tissue Core
Principal Investigator(s): Rajal Shah, MD

The goal of Prostate SPORE Tissue Core is to collect biological material with associated clinical information to facilitate translational research. The Tissue Core places patient confidentiality and clinical care as a top priority. As a coordinated effort between pathology, urology, and SPORE researchers, the Core has a developed a unified bioinformatics infrastucture (designated "Profiler") that provides researchers a wide range of annotated samples. To date, detailed information exists on over 1400 radical prostatectomy patients operated on at the University of Michigan between 1994-present. The specific goals of the Tissue Core include: (1) Protection of patient welfare. The highest priority is given to assure that no research protocol compromises pathology diagnosis or tumor staging. Patient confidentiality is maintained through use of an IRB-approved database protocol (2) Acquisition and processing of prostate tissues for research. The Core assures that the widest range of prostate tissues and derived biomolecules (i.e., protein, DNA and RNA) are available from several established and new sources. These include benign prostate tissue from patients without any known prostatic disease (cystoprostatectomy specimens and transplant donor prostates), clinically localized prostate cancer (U of M), metastatic hormone naïve prostate cancer (Ulm, Germany), and metastatic hormone refractory prostate cancer (Rapid Autopsy Program). (3) Maintenance of clinical and pathology data with links to molecular studies. The Tissue/Informatics Core will continue to expand the detailed clinical and pathology database conforming to the National Cancer Institute's Common Data Elements (CDE) guidelines, permitting queries between molecular findings and clinically relevant outcomes. (4) High quality pathologic review of prostate tissues. Expert pathologists assure uniform review of prostate tissue samples. (5) Pathology consultation for the purpose of designing translational research projects. This service focuses on determining the types of tissues and amount required for the successful completion of the projects. (6) Quality assessment of prostate tissues and clinical data. The Tissue Core staff regularly evaluates frozen and formalin fixed tissues for adequacy. (7) Development of technology appropriate for pathology based translational research. In this renewal, new biostatistical strategies are presented to evaluate biomarkers using tissue microarrays. Technologies such as quantitative real time PCR and laser capture microdissection protocols will be refined. In summary, the Tissue Core will provide SPORE investigators with a wealth of carefully annotated samples for translational research, while maintaining the highest level of clinical care.

Supplement
EMD121974 in Metastatic Androgen Independent Prostate Cancer
Principal Investigator: Maha Hussain, MD

Prostate cancer (PCa) is the second leading cause of cancer death in the USA. The primary cause of mortality is progression to androgen independence and hormone refractory status, which continues to pose a therapeutic dilemma. Despite best chemotherapy the median survival of this group of patients is about 18 months. The effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential, hence the importance of investigating alternative novel approaches.

EMD121974 is a potent selective integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities. The integrins ?v?3 and ?v?5 (vitronectin receptors) are involved in endothelial cell proliferation and migration, thus, are crucial molecules in the process of neovascularization. Blocking the ligation of vitronectin by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In PCa specifically, integrins are known to be molecules involved in PCa metastases with differential expression on tumor cells. Both tumors and vascular endothelial cells produce factors such a VEGF and bFGF that promote neovascularization, which have been implicated in prostate cancer progression. EMD121974 was shown to inhibit both ?v?3 and ?v?5 mediated cell adhesion and block in vitro endothelial cell migration. In Vivo experiments demonstrated the EMD121974 inhibited cytokine-induced, bFGF- and VEGF-mediated angiogenesis in a dose-dependent manner. EMD121974 also inhibited tumor growth in various in vivo systems. This randomized phase II trial is designed to evaluate the safety and efficacy of two dose levels of EMD121974: 500mg or 2,000mg IV twice weekly in patients with metastatic androgen independent PCa. Efficacy will be based on the rates of clinical progression at six-months. Secondary objectives include the rates of objective response and 50% or greater PSA decline in addition to correlative studies.

List of Investigators at the University of Michigan

Kenneth J. Pienta, M.D.
Principal Investigator
Co-Principal Investigator Project 5 and 6
University of Michigan
1400 E. Medical Center Drive
7303 CCGC
Ann Arbor, Michigan 48109-0946

Evan Keller, D.V.M., Ph.D.
Principal Investigator Project 1
University of Michigan
Comprehensive Cancer Center
1400 E. Medical Center Drive
5304 CCGC
Ann Arbor, Michigan 48109-0940

Arul M. Chinnaiyan, M.D., Ph.D.
Principal Investigator Project 3
University of Michigan
Department of Pathology
1301 Catherine St.
4237 Med Sci I
Ann Arbor, Michigan 48109-0602

Kathleen A. Cooney, M.D.
Co-Principal Investigator
Principal Investigator Project 4
University of Michigan
Comprehensive Cancer Center
1400 E. Medical Center Drive
7310 CCGC
Ann Arbor, Michigan 48109-0946

James E. Montie, M.D.
Co-Principal Investigator
Co-Principal Investigator Project 3
University of Michigan
1500 E. Medical Center Drive
3875 Taubman Center
Ann Arbor, Michigan 48109-0330

Diane M. Robins, Ph.D.
Principal Investigator Project 5
University of Michigan
1301 Catherine St.
3712 Med Sci II
Ann Arbor, Michigan 48109-0618

Shaomeng Wang, Ph.D.
Principal Investigator Project 6
University of Michigan
Comprehensive Cancer Center
1400 E. Medical Center Drive
3316 CCGC
Ann Arbor, Michigan 48109-0934

Martin Sanda, M.D.
Principal Investigator B Project 6
University of Michigan
Comprehensive Cancer Center
1500 E. Medical Center Drive
6217 CCGC
Ann Arbor, Michigan 48109-0944

Rajal Shah, M.D.
Tissue Core Director
Co-Principal Investigator Project 6
University of Michigan
Department of Pathology
1500 E. Medical Center Drive
2G332 University Hospital
Ann Arbor, Michigan 48109-0054

Jeremy MG Taylor, Ph.D.
Biostatistics Core Director
University of Michigan
Comprehensive Cancer Center
300 North Ingalls
Room 8D21
Ann Arbor, Michigan 48109-0473

Maha Hussain, M.D.
Principal Investigator Clinical Trial Supplement
University of Michigan
Comprehensive Cancer Center
1400 E. Medical Center Drive
7303 CCGC
Ann Arbor, Michigan 48109-0946

University of Michigan
S.P.O.R.E. in Prostate Cancer
Major Accomplishments and Publications

Kenneth J. Pienta

1. Kalikin LM, Schneider A, Thakur MA, Fridman Y, Griffin LB, Dunn RL, Rosol TJ, Shah RB, Rehemtulla A, McCauley LK, Pienta KJ. In Vivo Visualization of Metastatic Prostate Cancer and Quantitation of Disease Progression in Immunocompromised Mice. Cancer Biol Ther. 2003;2(6):656-660.
2. Tantivejkul, K., Kalikin, L., Pienta, K.J. Dynamic process of prostate cancer metastasis to bone. J Cell Biochem 91 (4): 706-17, 2004.
3. Cooper, C.R., Sikes, R.A., Nicholson, B.E., Sun, Y.X., Pienta, K.J., Taichman, R.S. Cancer cells homing to bone: the significance of chemotaxis and cell adhesion. Cancer Treat Res 118: 291-309, 2004.
4. Sikes, R.A., Nicholson, B.E., Koeneman, K.S., Edlund, N.M., Bissonette, E.A., Bradley, M.J., Thalmann, G.N., Cecchini, M.G., Pienta, K.J., Chung, L.W. Cellular interactions in the tropism of prostate cancer to bone. Int J Cancer 110(4):497-503, 2004.
5. Shah, R.B., Mehra, R., Chinnaiyan, A.M., Shen, R., Zhou, M., MacVicar, G.R., Varambally, S., Harwood, J., Bismar, T.A., Kim, R., Rubin, M.A., Pienta, K.J. Androgen Independent Prostate Cancer is a Heterogeneous Group of Diseases: Lessons from a Rapid Autopsy Program. Cancer Res 64(24): 9209-16, 2004.

Kathleen A. Cooney

1. Beebe-Dimmer JL, Wood DP, Gruber SB, Douglas JA, Bonner JD, Mohai C, Zuhlke KA, Shepherd C, Cooney KA: Use of complimentary and alternative medicine in men with a family history of prostate cancer: A pilot study. Urology, 63(2): 282-287, 2004.
2. Beebe-Dimmer JL, Wood DP, Gruber SB, Chilson DM, Zuhlke KA, Claeys GB, Cooney KA: Risk perception and concern among brother of men with prostate cancer. Cancer, 100(7): 1537-1544, 2004.
3. Douglas JA, Zuhlke KA, Beebe-Dimmer J, Levin AM, Gruber SB, Wood DP, Cooney KA. Identifying susceptibility genes for prostate cancer - A family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-?. Cancer Epidemiol Biomarkers Prev, 14(8):2035-2039, 2005. (should be LH Beta)

Evan Keller

1. Keller ET and J. Brown JM. Osteoprotegerin (OPG), receptor activator of NF?B ligand (RANKL) and RANK in cancer metastasis. Research Advances in Cancer 3:81-93, 2003.
2. Zhang J, Dai J, Yao Z, Lu Y, Dougall W, Keller ET. Soluble RANK-Fc diminishes prostate cancer progression in bone. Cancer Res. 63:7883-7890, 2003.
3. Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. Mar 1; 91(4):718-729, 2004.
4. Zhang J, Lu Y, Kitazawa R, Kitazawa S, Dai J, Zhao X, Yao Z, Pienta KJ, Keller ET. Role of TGF-ß in Prostate Cancer Skeletal Metastases: In Vivo Real-time Imaging of TGF-ß-induced RANK Ligand Transcriptional Activation in Prostate Cancer. Prostate. 59:360-369, 2004.
5. Keller ET. Mechanisms of bone resorption in prostate cancer skeletal metastases. In: F. Columbus, ed. Progress in Prostate Cancer Research. Nova Publishers. 2004.
6. Abraham Schneider, Linda M. Kalikin, Ana C. Mattos, Evan T. Keller, Matthew J. Allen, Kenneth J. Pienta, and Laurie K. McCauley. Bone Turnover Mediates Preferential Localization of Prostate Cancer in the Skeleton. Endocrinology, Apr 2005; 146: 1727 - 1736.

Arul M. Chinnaiyan

1. Yan, F., Sreekumar, A., Laxman, B., Chinnaiyan, A.M., Lubman, D.M. (2003) Protein Microarrays Using Liquid Phase Fractionation of Cell Lysates. Proteomics, 3(7):1228-35.
2. Kumar-Sinha, C. Rhodes, D.R., Chinnaiyan, A.M. (2003) Prostate Cancer Biomarkers: A Current Perspective, Expert Review for Molecular Diagnostics, 3(4): 459-70.
3. Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, Pienta KJ, Taichman RS. (2003) Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. Journal of Cell Biochemistry, 89(3):462-73.
4. Ghosh, D., Barrette, T.R., Rhodes, D., Chinnaiyan, A.M. (2003) Statistical issues and methods for meta-analysis of microarrays in prostate cancer. Functional Integrative Genomics, 3(4):180-8. Epub 2003 Jul 22.
5. Kleer , C.G., Cao, Q., Varambally, S., Shen, R., Ota, I., Tomlins, S.A., Ghosh, D., Sewalt, R.G., Otte, A.P., Hayes, D.F., Sabel, M.S., Livant, D., Weiss, S.J., Rubin, M.A., Chinnaiyan, A.M. (2003) EZH2 is marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proceedings of the National Academy of Sciences, 100(20):11606-11.
6. Kuefer, R., Hofer, M.D., Gschwend, J.E., Pienta, K.J., Sanda, M.G., Chinnaiyan, A.M., Rubin, M.A., Day, M.L. (2003) The role of an 80 kDa fragment of E-cadherin in the metastatic progression of prostate cancer. Clin Cancer Res., 9(17):6447-52.
7. Kunju, L.P., Rubin, M.A., Chinnaiyan, A.M., Shah, R.B.(2003) Diagnostic usefulness of monoclonal antibody P504S in the workup of atypical prostatic glandular proliferations. Am J Clin Pathol, 120(5):737-45.
8. Kumar-Sinha, C., Chinnaiyan A.M. (2003) Molecular markers to identify patients at risk for recurrence after primary treatment for prostate cancer. Urology 62(6 Suppl 2):19-35.
9. Kumar-Sinha, C., Shah, R.B., Laxman, B., Tomlins, S., Harwood, J., Schmitz, W., Conzelmann, E., Sanda, M.G., Wei, J.T., Rubin, M.A., Chinnaiyan, A.M. (2004) Elevated a-methylacyl-CoA racemase enzymatic activity in prostate cancer. Am J Pathol, (In press).
10. Sreekumar A, Laxman B, Rhodes, DR, Bhagavathula S, Giacherio D, Ghosh D, Sanda MG, Rubin MA, Chinnaiyan A.M. (2004) Protein Microarray Analysis Reveals that Prostate Cancer Patients Elicit a Humoral Immune Response to Alpha-methylacyl-CoA Racemase. JNCI, in press.
11. Scott A. Tomlins, Rohit Mehra, Rajal B. Shah, Eric Bruening, Vladimir Makarov, Arul M. Chinnaiyan. Development of a Non-T7 Based Whole Transcriptome Amplification Method for Gene Expression Profiling. (2004) Submitted. American Journal of Pathology.
12. Rajal B. Shah, M.D., Rohit Mehra, M.D., Arul M Chinnaiyan, M.D., PhD, Ming Zhou, M.D., PhD, Ronglai Shen, M.S., Jason Harwood, B.S., Tarek A. Bismar, M.D., Robert Kim, B.S., Mark A. Rubin, M.D., and Kenneth J Pienta, M.D. The Varied Morphological and Immunophenotypic Spectrum of Hormone Refractory Metastatic Prostate Cancer: Lessons from a Rapid Autopsy Program. Submitted, American Journal of Pathology.
13. Mark A. Rubin, Sooryanarayana Varambally, Rameen Beroukhim, Scott A. Tomlins, Daniel R. Rhodes, Pamela L. Paris, Matthias D. Hofer, Martina Storz-Schweizer, Rainer Kuefer , Jonathan A. Fletcher, Jennifer A. Byrne, Kenneth J. Pienta, Colin Collins, William R. Sellers, and Arul M. Chinnaiyan. Overexpression, Amplification and Androgen-regulation of TPD52 in Prostate Cancer. Cancer Research, in press, 2004.

Rajal Shah

1. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, Macvicar GR, Varambally S, Harwood J, Bismar TA, Kim R, Rubin MA, Pienta KJ. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004 Dec 15;64(24):9209-16.
2. Dhanasekaran SM, Dash A, Yu J, Maine IP, Laxman B, Tomlins SA, Creighton CJ, Menon A, Rubin MA, Chinnaiyan AM. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEB J. 2005 Feb;19(2):243-5. Epub 2004 Nov 17.
3. Shah RB, Kunju LP, Shen R, LeBlanc M, Zhou M, Rubin MA. Usefulness of basal cell cocktail (34betaE12 + p63) in the diagnosis of atypical prostate glandular proliferations. Am J Clin Pathol. 2004 Oct;122(4):517-23.
4. Das D, Shah RB, Imperiale MJ. Detection and expression of human BK virus sequences in neoplastic prostate tissues. Oncogene. 2004 Sep 16;23(42):7031-46.
5. Kumar-Sinha C, Shah RB, Laxman B, Tomlins SA, Harwood J, Schmitz W, Conzelmann E, Sanda MG, Wei JT, Rubin MA, Chinnaiyan AM. Elevated alpha-methylacyl-CoA racemase enzymatic activity in prostate cancer. Am J Pathol. 2004 Mar;164(3):787-93.
6. Sreekumar A, Laxman B, Rhodes DR, Bhagavathula S, Harwood J, Giacherio D, Ghosh D, Sanda MG, Rubin MA, Chinnaiyan AM. Humoral immune response to alpha-methylacyl-CoA racemase and prostate cancer. J Natl Cancer Inst. 2004 Jun 2;96(11):834-43. Erratum in: J Natl Cancer Inst. 2004 Jul 21;96(14):1112.
7. Scott A. Tomlins, Rohit Mehra, Rajal B. Shah, Eric Bruening, Vladamire Makarov, Arul M. Chinnaiyan. Development of Non-T7 Based Whole Transcriptome Amplification Method for Gene Expression Profiling. Submitted to Nucleic Acids Research.
8. Rubin MA, Varambally S, Beroukhim R, Tomlins SA, Rhodes DR, Paris PL, Hofer MD, Storz-Schweizer M, Kuefer R, Fletcher JA, Hsi BL, Byrne JA, Pienta KJ, Collins C, Sellers WR, Chinnaiyan AM. Overexpression, amplification, and androgen regulation of TPD52 in prostate cancer. Cancer Res. 2004 Jun 1;64(11):3814-22.
9. Kibel AS, Huagen J, Guo C, Isaacs WB, Yan Y, Pienta KJ, Goodfellow PJ. Expression mapping at 12p12-13 in advanced prostate carcinoma. Int J Cancer. 2004 May 1;109(5):668-72.
10. Siu W, Dunn RL, Shah RB, and Wei JT. Use of Extended Pattern Technique for Initial Prostate Biopsy. J Urol. 2005 Aug;174(2):505-9.
11. Sooryanarayana Varambally, Jianjun Yu, Bharathi Laxman, Daniel R. Rhodes , Rohit Mehra, Rajal B. Shah, Uma Chandran, Fedrico A. Monzon, Michael J. Becich, John T. Wei, Kenneth G. Pienta, Debashis Ghosh, Mark A.Rubin, Arul M. Chinnaiyan. Integrative Proteomic and Genomic Analysis of Prostate Cancer Progression. Cancer Cell. 2005 Nov;8(5):393-406.

Jeremy MG Taylor

Kalikin, L, Schneider A, Thakur M, Fridman Y, Griffin L, Dunn R, Rosol T, Shah R, Rehemtulla A, McCauley L, Pienta K. "In Vivo Visualization of metastatic prostate cancer and quantitation of disease progression in immunocompromised mice." Cancer Biology & Therapy, 2(6): 17-21, 2003.
Fu Z, Smith P, Zhang L, Rubin M, Dunn R, Yao Z, Keller E. "Effects of Raf Kinase Inhibitor Protein Expression on Suppression of Prostate Cancer Metastasis." Journal of the National Cancer Institute, 95(12): 878-89, 2003.
Ghosh, D, Barrette, T, Rhodes, D, Chinnaiyan, A: "Statistical Issues and Procedures for Meta-Analysis of Microarray Data: A Case Study in Prostate Cancer, Integrative Genomics 3, 180-188, 2003.
Taylor, JMG, Yu, M, Sandler, H: "Individualized Predictions of Disease Progression Following Radiation Therapy for Prostate Cancer." J Clin Oncol. 2005 Feb 1;23(4):816-25.
Shen R, Ghosh D, Chinnaiyan A: "Prognostic meta-signature of breast cancer developed by two-stage mixture modeling of microarray data." BMC Genomics 5: 94, 2004.
Rhodes D, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan A: "Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression." Proc Natl Acad Sci USA, 101: 9309-9314, 2004.
Ghosh D, Barette T, Rhodes D, Chinnaiyan A: "Statistical issues and methods for meta-analysis of microarray data: a case study in prostate cancer." Functional and Integrative Genomics 3: 180-188, 2003.
Beebe-Dimmer J, Wood D, Gruber S, Douglas J, Bonner J, Mohai C, Zuhlke K, Shepherd C, Cooney K: "Related Articles, Links Abstract Use of complementary and alternative medicine in men with family history of prostate cancer: a pilot study." Urology. 63(2):282-7, 2004.
Sarma A, McLaughlin J, Jacobsen S, Logie J, Dolin P, Dunn R, Cooney K, Montie J, Schottenfeld D, Wei J: "Longitudinal Changes in Lower Urinary Tract Symptoms Among a Cohort of Black American Men: The Flint Men's Health Study." Urology, 64(5): 959-65, 2004.
Chen B, Loberg R, Olson K, Thakur M, Neeley C, O'Hara S, Qweitzig D, Gross S, Doyle G, Terstappen L, Dunn R, Kalikin L, Pienta K. "Preliminary Study of Immunomagnetic Quantification of Circulating Tumor Cells in Patients with Advanced Disease." Urology. 2005 Mar; 65(3):616-21.
Claeys G, Sarma A, Dunn R, Zuhlke K, Montie J, Wojno K, Schottenfeld D, Cooney K. "INS PstI Polymorphism and Prostate Cancer Diagnosis in African-American Men." Prostate, 2005 Sep 15;65(1):83-7.
Fu Z, Kitagawa Y Shen R, Shah R, Mehra R, Rhodes D, Mizokami A, Dunn R, Chinnaiyan A, Keller E. "The Metastasis Suppressor Gene Raf Kinase Inhibitor Protein is a Novel Prognostic Biomarker of Prostate Cancer Recurrence". Prostate. 2005 Sep 20.

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