SPOREs : Organ-Specific SPORE Programs : Prostate

Johns Hopkins Prostate Cancer SPORE Program Description

A. Introduction

(1) Purpose and Intent of the Johns Hopkins Prostate Cancer SPORE Program

Prostate cancer has become one of the most frequently diagnosed cancers in men in the United States (US) and a major cause of cancer morbidity and mortality.  Over the past decade and a half, dedicated prostate cancer research, accomplished by Johns Hopkins Prostate Cancer SPORE investigators and other researchers, has led to a remarkable accumulation of knowledge about the molecular mechanisms by which human prostate cancers arise and progress to threaten life.  To improve screening, early detection, diagnosis, prevention, and treatment of prostate cancer, these new insights into prostate cancer molecular biology need to be translated into new hypotheses for testing in population studies and in clinical trials.  The transcendent objective of the Johns Hopkins Prostate Cancer SPORE is to reduce prostate cancer incidence and mortality via the focused pursuit of translational research in prostate cancer.

The National Cancer Institute (NCI) has defined translational research for the SPORE program as “[using] the knowledge of human biology to develop and test the feasibility of cancer-relevant interventions in humans and/or [determining] the biological basis for observations made in individuals with cancer or in populations at risk for cancer.”  During its initial funding period under the leadership of Donald S. Coffey, Ph.D., and in the most recent funding period under the leadership of William G. Nelson, M.D., Ph.D., the Johns Hopkins Prostate Cancer SPORE Program has emerged as a major center for translational research in prostate cancer, successfully promoting (i) the identification of new methods for prostate cancer risk assessment, (ii) the application of new strategies for prostate cancer screening, (iii) the discovery of new molecular biomarkers for prostate cancer diagnosis, detection, and prognosis, (iv) the development of new opportunities for prostate cancer prevention, and (v) the introduction of new approaches to prostate cancer treatment, including the use of endothelin receptor antagonists, replication-restricted adenoviruses, and genetically-modified prostate cancer cell vaccines.  Since the last competitive renewal application, the Johns Hopkins Prostate Cancer SPORE Program Investigators and other Prostate Cancer Program researchers have produced some 376 published manuscripts.  To accomplish its translational research mission, the Johns Hopkins Prostate Cancer SPORE Program has succeeded in establishing a productive research team by recruiting a diverse collection of dedicated prostate cancer researchers from the Departments of Urology, Oncology, Pathology, Radiation Oncology, and Radiology in the Johns Hopkins University School of Medicine, as well as from the Departments of Environmental Health Sciences and Epidemiology in the Johns Hopkins Bloomberg School of Public Health, and by identifying and mentoring talented new prostate cancer researchers through Career Development initiatives.  The SPORE Program has also succeeded in creating critical Core Resources, which, along with other dedicated institutional resources, have been exploited to support the critical mass of translational researchers, and in establishing productive interactions with other funded Prostate Cancer SPORE Programs at other institutions. 

For the future, the Johns Hopkins Prostate Cancer SPORE Program aims to build on track record of success to further its translational research agenda.  With support from the Patrick C. Walsh Prostate Cancer Research Fund, a $1,000,000 institutional commitment to the SPORE Program goals, and from the SPORE Program Career Development and Developmental Research Programs, the SPORE Program leadership team, William G. Nelson, M.D., Ph.D., serving as Principal Investigator, and Robert H. Getzenberg, Ph.D., serving as Co-Principal Investigator, has assembled a vibrant pipeline of new prostate cancer translational research opportunities.  This ample pipeline has enabled the Johns Hopkins SPORE Program to remain true to the SPORE goal of “…[reaching] the feasibility testing stage in humans within the anticipated 5-year period of grant support…”: each of the current SPORE Projects will have achieved this goal by the spring of 2008.  For this SPORE Program renewal application, a collection of six new translational Research Projects emerging from the discovery pipeline, three Core Resources, two Developmental Research Projects, and two Career Development Projects, has been assembled to best exploit the most recent advances in the understanding of prostate cancer molecular biology, to best apply the most modern research technology to human prostate cancer, and to best accelerate the introduction of innovative new approaches for prostate cancer screening, early detection, diagnosis, prevention, and treatment.

(2) Scientific Capabilities of the Johns Hopkins Prostate Cancer SPORE Program

Historically, prostate cancer research at Johns Hopkins was anchored in the Department of Urology of the School of Medicine, with small research efforts present in the Departments of Oncology and Pathology.  Throughout the duration of the Johns Hopkins Prostate Cancer SPORE Program, prostate cancer research activities have grown substantially in the Departments of Urology, Oncology, and Pathology, and have begun to appear in other academic Departments at the School of Medicine, and at the Bloomberg School of Public Health.  Currently, among the faculties of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, spread throughout eight academic Departments (School of Medicine: Oncology, Urology, Pathology, Radiology, Radiation Oncology, Pharmacology, and Radiology; School of Public Health: Environmental Health Sciences and Epidemiology), are 33 full-time faculty who conduct prostate cancer research, with expertise in all aspects of prostate cancer.  In the Departments of Urology, Oncology, Radiation Oncology, and Pathology, there are 20 full-time faculty who deliver prostate cancer care.  For all of these reasons, Johns Hopkins has become an internationally recognized center of research and clinical excellence for prostate cancer.  Furthermore, the ongoing Johns Hopkins Prostate Cancer SPORE Program has stimulated the growth of prostate cancer research at Johns Hopkins, and has provided a means by which the diverse and productive group of faculty investigators throughout the Johns Hopkins community can coordinate their translational research activities.

The Departments of Urology, Oncology, Pathology, and Radiation Oncology at the Johns Hopkins University School of Medicine each possess internationally-recognized productive programs in prostate cancer (see Table 1).  For the Department of Urology, prostate cancer has been a major clinical and research interest for more than two decades.  The Department Chairman, Dr. Alan W. Partin, and Research Director, SPORE Co-Principal Investigator Dr. Robert H. Getzenberg, are major leaders in field of prostate cancer research.  Twelve full-time faculty members of the Department conduct prostate cancer research; major research projects are underway to identify inherited susceptibility genes for familial prostate cancer, where Dr. William B. Isaacs serves as the Chairman of the International Consortium for Prostate Cancer Genetics, to characterize somatic genome abnormalities and changes in gene expression in prostate cancer cells, to develop new gene therapy approaches for prostate cancer treatment, and to discover and test new biomarkers for prostate cancer for prostate cancer screening, detection, and diagnosis (Dr. Alan W. Partin operates a Clinical and Epidemiologic Center as part of the NCI Early Detection Research Network).  Drs. Alan W. Partin, Robert H. Getzenberg, Shawn E. Lupold, and Bruce J. Trock will serve as Prostate Cancer SPORE Program Research Project Co-Principal Investigators or Core Resource Co-Directors (Table 2).  Drs. Patrick C. Walsh, H. Ballentine Carter, Robert W. Veltri, Ronald Rodriguez, and Donald S. Coffey remain active contributors to the Prostate Cancer Research Program; newly recruited faculty members, Edward M. Schaeffer and Mark L. Gonzalgo, are physician-scientists focused on prostate cancer translational research.  Specialized equipment and resources are available in the Department of Urology for cDNA microarray/transcription profiling, for high-throughput genotyping and DNA sequencing, and for proteomics analyses using mass spectrometry. 

In the Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, 8 full-time faculty members conduct prostate cancer research.  Drs. William G. Nelson and Michael A. Carducci serve as Co-Leaders of the Prostate Cancer Program at the Cancer Center, a peer-reviewed Program, rated Outstanding to Excellent upon peer review, supported by an NCI Cancer Center Support Grant.  Dr. Carducci, a prostate cancer expert, also serves as Co-Leader of the Chemical Therapeutics Program and Principal Investigator of the NCI-supported Phase 1 Drug Development Contract.  The Chemical Therapeutics Program houses the Analytical Core Pharmacology Laboratory (under the direction of Michele A. Rudek, Pharm. D.), equipped with liquid chromatography and mass spectroscopy capabilities to permit pharmacokinetic monitoring of anti-neoplastic drugs in preclinical and clinical trials.  Research projects are underway in the Cancer Center to develop new immunotherapies and gene therapies for prostate cancer, to test new anti-angiogenesis treatments for prostate cancer, to explore new strategies for restoring epigenetically “silenced” gene expression in prostate cancer, and to develop new prostate-specific “pro-drugs” for selective killing of prostate cancer cells.  Along with Drs. Nelson and Carducci, Drs. Samuel R. Denmeade, John T. Isaacs, Roberto Pili, Srinivasan Yegnasubramanian, and Charles G. Drake, each with interests in translational research in prostate cancer, are Co-Principal Investigators of Prostate Cancer SPORE Program Research Projects.  Dr. Mario A. Eisenberger has focused his attention on late-stage clinical trials designed to establish the standard-of-care for advanced prostate cancer.  Also, in addition to the Analytical Pharmacology Core, the SKCCC at Johns Hopkins has a number of other Core Facilities, providing cDNA microarray/transcription profiling, animal care and use, flow cytometry, bioinformatics, medicinal chemistry, and GMP viral vector and vaccine cell production and expansion capabilities. 

For the Department of Pathology, Dr. Jonathan I. Epstein serves as Deputy Director of Surgical Pathology, and Dr. Daniel W. Chan serves as the Director of Clinical Chemistry.  Along with Drs. Angelo M. De Marzo, David M. Berman, George J. Netto, and Alan K. Meeker, each directs the majority of his research attention to prostate cancer.  The Department of Pathology and the Cancer Center support several dedicated research capabilities, including a tissue microarray facility (directed by Dr. Angelo De Marzo, an investigator primarily interested in prostate cancer), blood and tissue biospecimen archives, several immunohistochemistry laboratories (one directed by Dr. De Marzo), a clinical chemistry facility, and a proteomics laboratory (directed by Dr. Chan).  Drs. De Marzo and Netto will serve as Prostate Cancer SPORE Program Core Co-Directors.  The newly-created Department of Radiation Oncology, has as its Chairman, Dr. Theodore L. DeWeese, a Co-Principal Investigator for two SPORE Program Research Projects.  Dr. Danny Y. Song is a committed radiation therapy clinical researcher focused on improving prostate cancer treatment.  The Department of Radiation Oncology has developed specialized instrumentation for shaping radiation fields to permit small animal external beam radiation therapy.  Finally, in addition to the standing prostate cancer research programs at the Johns Hopkins University School of Medicine, over the past few years, partly supported by SPORE Developmental Research funds, new prostate cancer research initiatives have appeared in the Department of Radiology and at the Bloomberg School of Public Health.  Radiology researchers Drs. Martin G. Pomper and Zaver M. Bhujwalla have committed significant effort to the development of new molecular imaging strategies for prostate cancer, for both PET and MRI platforms.  Dr. Elizabeth A. Platz in the Department of Epidemiology at the Bloomberg School has and will continue to be a major Prostate Cancer SPORE contributor, and Dr. Jean G. Ford, with a research interest in health disparities, has been recruited to lead a major Program at the School of Public Health and Cancer Center focused on disparities in cancer, including prostate cancer.  He has established a community-based research program targeting underserved populations that includes prostate cancer screening services.

Table 1.  Prostate Cancer Research Capabilities at Johns Hopkins: Published Manuscripts on Prostate Cancer

1. Urology, Oncology, Radiation Oncology, and Pathology are in the Johns Hopkins University School of Medicine, Epidemiology is in the Johns Hopkins University Bloomberg School of Public Health
2. from PubMed
3. h number of manuscripts cited at least h times, ISI Web of Science®
4. SPORE Program Research Project Co-Principal Investigator
5. SPORE Program Core Resource Co-Director
6. New recruit to Johns Hopkins faculty since last SPORE competitive renewal.

(3) Organization of the Johns Hopkins Prostate Cancer SPORE Program to Maximize the Potential of Johns Hopkins to Achieve Translational Research Objectives

With substantial prostate cancer research capability and intensive prostate cancer research focus, distributed throughout the Departments of Urology, Oncology, Radiation Oncology, and Pathology in the Johns Hopkins University School of Medicine, as well as at the Bloomberg School of Public Health, the Johns Hopkins Prostate Cancer SPORE Program has been organized to best coordinate these research efforts toward translational research objectives.  New prostate cancer patients present to Johns Hopkins via the Departments of Urology, Radiation Oncology, and Oncology, blood and body fluid testing for these patients is accomplished via the Division of Laboratory Medicine of the Department of Pathology, and prostate tissue specimens are processed via the Division of Surgical Pathology in the Department of Pathology.  Large epidemiology study populations and community outreach and screening activities are managed at the School of Public Health.  The SPORE Program Principal Investigator, Dr. William G. Nelson, has a faculty appointment in each of the key Departments at the School of Medicine and an appointment at the School of Public Health, directs the Prostate Cancer Program at the SKCCC, runs a prostate cancer research laboratory, cares for prostate cancer patients, act as the Associate Director for Translational Research in the Cancer Center, is the Principal Investigator of the NCI-funded Molecular Targets Training Grant (T32 CA09071) focused on post-doctoral training in translational research, is a Co-Principal Investigator and conducts translational research in prostate cancer.  Each of the SPORE Program Research Projects is directed by two Co-Principal Investigators, often from different academic Departments, in such a way as to ensure translation of prostate cancer biology discoveries to population study questions and/or clinical trial hypotheses.  Core Resources, with Co-Directors drawn from different Departments, have been assembled to develop new prostate tissue biomarkers for use in clinical trials and epidemiology studies (Tissue Archive Core), and to help define populations for biomarker validation/assessment studies and prostate cancer patient cohorts for “proof-of-principle” clinical trials (Biostatistics Core).   An administrative structure (see below), supported by an Administrative Core, has been established to coordinate interactions between Departments, between Research Projects and Cores, between Prostate Cancer SPOREs at other institutions, and with the NCI.

Table 2.  Organization of the Johns Hopkins Prostate Cancer SPORE Program Across Academic Departments to Best Promote Translational Research.

(4) Johns Hopkins Prostate Cancer SPORE Progress Report

It is alarming to realize that in the past 65 years, from 1941 to 2006, only eight major discoveries have ever made the translation into accepted standard medical practice for the diagnosis and treatment of prostate cancer: (i) androgen deprivation/anti-androgen therapy, (ii) core needle biopsies, (iii) Gleason pathological grading, (iv) serum levels of prostate-specific antigen (PSA), (v) improvements in radical prostatectomy technique (anatomic approach, nerve sparing, reduced incontinence, and reduced blood loss), (vi) improved delivery of radiation therapy through conformal and brachytherapy approaches, (vii) bisphosphonate treatment for osteoporosis associated with androgen-deprivation and for prevention of skeletal complications of progressive prostate cancer bone metastases, and (viii) docetaxel-based chemotherapy for androgen-independent metastatic prostate cancer.

This lack of clinical progress has occurred despite the publication of over 58,000 research papers on prostate cancer over the past 45 years (listed in PubMed for the period 1960-2006).  Indeed, all eight clinical advancements originated primarily from clinical research.  To overcome this barrier to clinical translation, the Johns Hopkins Prostate Cancer SPORE Program has focused its research on resolving major clinical problems within the field of prostate cancer, investigating these problems in research laboratories located in clinical Departments, with an emphasis on strong science and its translation to the clinic.  The following is a limited list of some of the progress that has been made through translational research supported thus far by the Johns Hopkins Prostate Cancer SPORE grant award, followed by brief highlights of the progress made so far by each of the currently funded SPORE Research Projects, a description of translational research science careers developed by the SPORE Program, and selected manuscripts published between 2002-2006 by SKCCC Prostate Cancer Program investigators supported by the SPORE and/or the Patrick C. Walsh Prostate Cancer Research Fund.

Major Translational Research Achievements of the Johns Hopkins Prostate Cancer SPORE Program

(i) Development of prostate cancer risk stratification tools to aid in prostate cancer screening, diagnosis, staging, treatment selection, and prognosis.

SPORE investigator Dr. Alan W. Partin and his colleagues developed the now widely-used “Partin Tables” to help physicians make recommendations regarding appropriate therapeutic options.  The predictions in the “Tables” reflect the likelihood of having organ-confined prostate cancer, based on
PSA levels, Gleason grade on prostate biopsy, and clinical staging.  The data contained within the “Tables” were derived using stringent statistical analyses of data from thousands of men with prostate cancer developed by SPORE Biostatistics Core Director Dr. Steve Piantadosi, and have been validated and expanded by collaborative interactions between the Johns Hopkins Prostate Cancer SPORE Program and SPORE Programs at the Baylor College of Medicine, the University of Michigan, as well as by collaborations with several other institutions.  The “Partin Tables,” now one of the most commonly-used clinical tools for prostate cancer management, are often carried in the pockets of prostate cancer practitioners, aiding these physicians in counseling prostate cancer patients in choice of treatment.  The “Tables” can be easily understood by patients, are actively sought on the internet, and appear in numerous sources of lay literature.  Newly-updated “Partin Tables” are now being formulated, encompassing the use of various new strategies for PSA testing (free PSA, bound PSA, PSA isoforms, etc.), and featuring improved pathological analysis (including extent of cancer and number of positive needle biopsies, nuclear morphometric grade, etc.)  Treatment outcome results are being correlated with pre-surgical data, using new statistical and neural-network models, to deliver ever more precise information for individual prostate cancer patients.  The future availability of new molecular biomarkers, derived from cDNA microarray studies, CpG island hypermethylation profiles (Research Project #5 in this SPORE application), and other experimental approaches, may permit even more improvements to the “Partin Tables.”

In several landmark papers from this SPORE, the largest and most complete studies of prostate cancer patients with rising serum PSA after radical prostatectomy have been reported, providing the new “Pound Tables.”  The “Partin Tables” used pre-operative clinical data to predict findings at the time of surgery; the “Pound Tables” used post-operative data to predict the natural history of prostate cancer after surgery.  Studies of the natural history of prostate cancer recurrence after surgery have found that on an average it took a man eight years from the time the serum PSA began to rise until he developed metastatic disease.  Furthermore, if prostate cancer metastases appeared more than seven years after surgery, men had a 70% chance of being alive seven years later.  The “Pound Tables” use the pathological Gleason score, the time it takes for PSA to come back after surgery, and the serum PSA doubling time, to predict the likelihood of developing metastatic disease.  “Pound Tables” data are invaluable for translational research: men with a rising serum PSA after surgery at high risk for developing prostate cancer metastases can be specifically targeted for clinical trials of new prostate cancer treatments.  Like the “Partin Tables,” the “Pound Tables” are commonly used by practicing physicians and commonly sought on the internet by prostate cancer patients. 

One of the major translational contributions from the Johns Hopkins Prostate Cancer SPORE Program included the introduction of the concept of the utility of serum PSA changes over time (“PSA velocity”) to prostate cancer detection, diagnosis, and risk stratification.  This concept emerged from a study of serum samples collected from some 1,500 male subjects participating in the Baltimore Longitudinal Study of Aging (BLSA) at the National Institute of Aging, led by SPORE investigator Dr. H. Ballentine Carter.  As part of periodic BLSA evaluations, serum samples had been collected serially over as many as 20 years, frozen, and stored.  By identifying men who were subsequently diagnosed with prostate cancer, who were found to have benign prostatic hyperplasia (BPH), or who had no clinically significant prostate diseases, the temporal patterns of serum PSA fluctuations associated with BPH and with prostate cancer were determined.  Before diagnosis, men with prostate cancer displayed a consistent increase in serum PSA levels over three determinations, separated by 18 months, of over 0.75 ng/mL per year. This permitted the identification of men with prostate cancer before PSA levels exceeded 4.0 ng/mL via determination of the “PSA velocity.”  Increases in “PSA velocity” were found to precede the diagnosis of localized prostate cancer by digital rectal examination by an average of seven years.  “PSA velocity” has become a commonly used clinical tool for prostate cancer screening.  Additional studies using the BLSA cohort found that when the “free PSA” level was lower than 15% of the “total PSA” level, men were at risk for aggressive prostate cancer, and this serum abnormality could be detected up to 15 years before prostate cancer diagnosis.  Men with less aggressive prostate cancer tended to have “free PSA” levels greater than 15% of the “total PSA” level. 

While PSA testing is widely used in the screening and early detection of prostate cancer in the US, efforts to establish and refine PSA screening guidelines are still underway.  Ideally, such guidelines must reflect the burden of screening in the population in terms of unnecessary tests, false-positive and false-negative tests, and the consequences of false-positive tests.  The BLSA serum bank, containing longitudinally collected blood specimens, along with associated long-term follow-up clinical data and dietary histories from BLSA participants, is a unique resource that has been made available as a result of a productive collaboration between Prostate Cancer SPORE investigator Dr. H. Ballentine Carter and Drs. Mitchell Harmon and Reuben Andres at the National Institute of Aging, to tackle this critical clinical problem.  Recent studies have focused on BLSA patients who have been continuously screened for the presence or absence of prostate disease with questionnaires, physical examination, magnetic resonance imaging, PSA measurements, and prostate biopsies (when indicated).  Some 5820 serum PSA determinations have been conducted on serum specimens from 1054 male BLSA participants; 143 (13.6%) of the men have ultimately been diagnosed with prostate cancer.  Using a Markov model, a strategy of serum PSA testing at ages 40 and 45, followed by PSA testing every two years beginning at age 50, would both reduce prostate cancer mortality and the number of prostate cancer biopsies, when compared to the currently used strategy of PSA testing each year beginning at age 50.  Furthermore, use of a serum PSA level threshold for prostate biopsy below 4.0 ng/mL or use of “age-specific” serum PSA threshold levels, did not appear better than use of a PSA threshold of 4.0 ng/mL.  Thus, annual PSA screening beginning at age 50 years may be less effective and more resource-intensive than a PSA screening strategy that begins at an earlier age but screens biennially instead of annually.  Dr. Carter and his colleagues also evaluated the long-term risk of prostate cancer over 3 decades in young men as a function of serum PSA levels.  Their analysis revealed that the relative risk of prostate cancer for men 40-49.9 years of age was 3.65 (1.56-8.55) when serum PSA levels were at or above the median (0.60 ng/mL) compared to men with serum PSA levels below the median.  The risk was similar for men aged 50-59.9 years when comparing men with PSA levels above and below the median (0.71 ng/mL).  At 25 years, the cumulative probability of freedom from prostate cancer for men aged 40-49.9 years was 89.6 percent (81-97) and 71.6 percent (60-83) when PSA levels were below and above the median, respectively.  The 25-year disease-free probability for men aged 50-59.9 years was 83.6 percent (76-91) and 58.9 percent (48-70) when PSA levels were below and above the median, respectively.  These data demonstrate the long-term risk of prostate cancer for young men who have normal PSA levels, and suggest that risk stratification based on PSA level may be useful to determine the appropriate intensity and intervals for screening, and selection of men for future prostate cancer prevention trials.

(ii) Exploration of the role of chronic or recurrent inflammation in prostatic carcinogenesis.

Chronic or recurrent inflammation, especially when combined with carcinogen exposure, is well known to cause cancers in many different organ sites.  Not surprisingly perhaps, evidence from prostate cancer epidemiology, genetics, and histopathology, collected in pursuit of Prostate Cancer SPORE Projects, has converged to also implicate inflammation, perhaps triggered or perpetuated by some sort of infection, in the earliest steps in the pathogenesis of prostate cancer.  Data collected from autopsies of men in Asia and in the US by SPORE investigator Dr. Angelo M. De Marzo has suggested that prostate inflammation is substantially more common in the US than in Asia, appears at a relatively young age in the US, and is seen in the peripheral zone in very nearly all prostates from men in the US.  Prostatitis and pelvic pain syndrome, a symptom complex of irritative voiding and pelvic discomfort, may affect as many as 9% of men between ages 40-79 years.  The origin of this syndrome, its association with infectious agents, and its relationship to degree, intensity, or anatomy of inflammation in the prostate, has been difficult to elucidate.  Nonetheless, associations between prostatitis and pelvic pain syndrome and prostate cancer have been detected in epidemiological studies.  However, these associations may be confounded by bias, as men with urinary symptoms may be more likely to be referred to urologist and undergo screening for prostate cancer.  Genitourinary infections, caused by a variety of different pathogens, have also been correlated with the prostate cancer risk in some but not all population studies.  The mechanism may be substantially different from the way in which human papillomaviruses cause uterine cervix or oral cancers: pathogens associated with prostate cancer appear more likely to trigger neoplastic transformation indirectly, via induction of inflammatory responses replete with genome damaging reactive oxygen and nitrogen species, than by directly commandeering prostate cells through expression of pathogen-produced transforming proteins.  In support of this notion, a team of Prostate Cancer SPORE investigators, including Drs. Elizabeth A. Platz, William G. Nelson, William B. Isaacs, and Angelo M. De Marzo, found that pathogens eliciting exudative inflammatory responses increased serum PSA values in young men (median age of 28 years), hinting at damage to the barrier function of the prostate epithelium.

Prostate cancers are well-known to cluster in some families, but whether each of familial case of prostate cancer reflects inherited susceptibility, a pooled exposure, a combination of inherited vulnerability to a shared exposure, or some sort of disease detection bias, has been difficult to ascertain.  Also, whether common genetic variants, or rare disease genes, or both, will account for inherited prostate cancer susceptibility, has not been determined.  Twin studies, examining differences in cancer rates between monozygotic and dizygotic twins, have described a greater contribution of inheritance to prostate cancer development than to the development of any other cancer, estimating that some 42% of all prostate cancers may have a genetic component.  With this strong genetic contribution to prostate cancer development, genetic mapping studies of hereditary prostate cancer, defined as having three or more first-degree relatives diagnosed with prostate cancer, or as having two or more brothers with prostate cancer diagnosed at age 55 years or younger, have been led by SPORE investigator Dr. William B. Isaacs, the Principal Investigator of the International Consortium for Prostate Cancer Genetics, an effort providing a major node for inter-SPORE collaboration with Prostate Cancer SPORE investigators from the Fred Hutchinson Cancer Research Center, the University of Michigan, and Northwestern University.  Two of the genes that have been found, RNASEL at chromosome 1q24-25 and MSR1 at chromosome 8p22-23, appear to function in host regulation of inflammatory responses to infection: RNASEL encodes a nuclease that can be activated by interferon to degrade viral RNA upon viral infection, and MSR1 encodes subunits of a macrophage receptor for bacterial lipopoylsaccharide and lipoteichoic acid.  In addition, common variants of a number of other genes encoding participants in host inflammatory responses to infections, including TLR4 and other members of toll-like receptor signaling pathways, MIC-1, IL1-RN, and COX-2, have also been associated with prostate cancer risk. 

Can interactions between inflammatory genes and exposures to certain pathogens underlie the risk of prostate cancer development?  Provocative data have been reported by reseachers at the Cleveland Clinic to suggest that men with RNASEL defects are more susceptible to chronic infections with a previously unrecognized gamma-retrovirus, xenotropic murine leukemia virus-related virus (XMRV).  Whether XMRV acts to promote prostate cancer has not yet been determined, but as a general mechanism, the interplay between genetic susceptibility and specific pathogen exposure may well prove critical to a number of prostate diseases, including prostatitis and pelvic pain syndrome, benign prostatic hyperplasia, and prostate cancer. 

Proliferative inflammatory atrophy (PIA), a prostate cancer precursor lesion described by SPORE investigator Dr. Angelo M. De Marzo, offers strong evidence for a direct association between prostatic inflammation and prostate cancer.  PIA lesions, which are often found adjacent to prostatic intraepithelial neoplasia (PIN) lesions and prostatic carcinomas, are characterized by rapidly dividing epithelial cells that express molecular markers of stress and do not fully differentiate.  These PIA lesions likely arise in response to some sort of damage to the prostate epithelium, accompanied by epithelial regeneration.  Many types of prostatic epithelial damage may promote the appearance of PIA.  PIA lesions have been described in rats exposed to the prostate carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic aromatic amine found in charred meats.  In addition, Chlamydia antigens have been detected in some inflamed atrophic prostate lesions.  As of yet, whether the inflammatory responses seen at or near PIA lesions are directly responsible for injury to the epithelium, arise in response to epithelial damage, or both, has not been fully resolved.  Nonetheless, compelling data support the notion that at least some PIA lesions are prostate cancer precursors: as many as 5-10% of PIA lesions have been found to contain genome defects known to be present in prostate cancers. 

If their new model for prostatic carcinogenesis is correct, Drs. De Marzo, Nelson, Isaacs, Platz, and others may have provided an opportunity for considering a number of potential prostate cancer prevention strategies.  Selenium and vitamin E might be expected to provide protection against oxidant damage inflicted in association with chronic prostatic inflammation, and thus protect against prostate cancer development and progression.  Sulforaphane, an inducer of carciogen-detoxification and anti-oxidant enzymes, might also be effective at preventing prostate cancer morbidity and mortality.  This last possibility was developed and successfully taken to human clinical trials in one of the Research Projects conducted during the last SPORE Program funding  period.

(iii) Vaccine immunotherapy for prostate cancer.

The first clinical trial of prostate cancer cells, genetically-engineered to express high levels of GM-CSF, as prostate cancer vaccines was conducted by the Johns Hopkins Prostate Cancer SPORE Program.  This strategy was developed all the way from the conceptual level, through preclinical animal studies, through Food and Drug Administration (FDA) and Recombinant DNA Advisory Committee (RAC) approvals, and into phase 1 clinical trials, by a team of SPORE Program Investigators, including Drs. Drew M. Pardoll, Jonathan W. Simons, Richard C. Mulligan, and William G. Nelson.  The first clinical study, involving the creation of prostate cancer vaccine cells via transfer of GM-CSF cDNA into autologous prostate cancer cells recovered at radical prostatectomy, indicated that the vaccine strategy was safe, and appeared capable of stimulating immune responses against prostate cancer.  Unfortunately, the autologous vaccine cells expressed variable levels of GM-CSF and could only be produced in limited quantities.  Nonetheless, when these cells were radiated and administered as vaccines, measurable immune responses, manifest as activation of delayed-type hypersensitivity (DTH) reactions against unmodified autologous prostate cancer cells, were evident.  Side effects were limited to skin reactions (swelling, erythema, etc.) at vaccination sites. 

With these early clinical findings of promising immunological activity but variable and limited vaccine preparations, the autologous vaccine strategy was abandoned in favor of using allogeneic prostate cancer cell vaccines, which could be produced in a standardized manner, in limitless quantities, and without the need for surgical harvest of cancer cells.  The well-known prostate cancer cell lines, LNCaP and PC-3, were selected for manufacture as vaccine cells because of the broad array of potential cancer antigens expressed by the two cells together.  The resultant vaccine cell preparations expressed stable levels of GM-CSF and could be used to treat men with prostate cancer at any stage of disease progression.  The first trial of this immunotherapy strategy, also serving as the first trial of any allogeneic GM-CSF-secreting cancer vaccine, was conducted in men (n = 21) with prostate cancer and a rising serum PSA value after radical prostatectomy.  The treatments regimen featured weekly via intradermal injections of 1.2 x 108 GM-CSF gene-transduced, irradiated, cancer cells (6 x 107 each of LNCaP cells and PC-3 cells) for 8 weeks.  The findings were acceptable toxicities, again largely limited to local injection-site reactions with occasional flu-like symptoms.  Provocatively, one of the vaccinated men exhibited a significant decline in serum PSA for at least 7 months, while 76% of all treated men showed a statistically significant decrease in PSA velocity (slope) when compared with pretreatment (p < 0.001).  Biopsies of vaccination sites revealed infiltration by CD1a+ dendritic cells and CD68+ macrophages, a finding similar to the that seen using autologous GM-CSF-transduced cancer cell vaccines.  Most remarkably, following vaccination, the treated men also exhibited measurable antibody responses against at least five antigens present in LNCaP or PC-3 cells, with high-titer antibody responses detected against a 250-kDa antigen expressed by normal prostatic epithelial cells in the man who enjoyed a serum PSA decline during his partial remission, and reduced titers of this antibody detected upon ultimate PSA progression.

The development of allogeneic cancer cell vaccines for prostate cancer, led initially by Johns Hopkins SPORE Investigators Drs. William G. Nelson and Jonathan W. Simons, has progressed to pivotal multi-center phase 3 clinical trials as GVAX®, sponsored by Cell Genesys Incorporated, an example of a successful “hand-off” of SPORE technology for commercial development.  With the early clinical trial results, Cell Genesys refined and perfected the manufacture of prostate cancer GVAX®, and has pursued commercial development of this immunotherapy strategy in multi-center clinical trials, including two U.S. FDA regulatory trials, VITAL-1, a phase 3 randomized, open-label study of prostate cancer GVAX® versus docetaxel and prednisone in men with metastatic hormone-refractory prostate cancer who have not yet received chemotherapy, and VITAL-2, a phase 3 randomized, open-label study of docetaxel in combination with prostate cancer GVAX® versus docetaxel and prednisone in taxane-naïve men with metastatic hormone-refractory prostate cancer with pain.  In addition, combinations of prostate cancer GVAX® and anti-CTLA4 antibodies, to help overcome cancer-associated immune tolerance, are planned in the future to likely involve NCI Prostate Cancer SPORE investigators from Memorial Sloan-Kettering, University of California-San Francisco, MD Anderson, and Johns Hopkins.  Finally, in an effort to translate a basic immunology finding concerning reduced prostate cancer immune tolerance barriers following androgen deprivation therapy reported last year by former Johns Hopkins Prostate Cancer SPORE Career Development Investigator Charles G. Drake, M.D., Ph.D., a clinical trial of prostate GVAX® vaccines, given along with LHRH analog treatment to men with metastatic prostate cancer, has been endorsed by the Eastern Cooperative Oncology Group.  Further improvements in prostate cancer vaccine immunotherapy will be pursued by Drs. Charles G. Drake and Theodore L. DeWeese in a Research Project proposed as part of the current SPORE Program competitive renewal application.

(iv) PSA-selective, replication-restricted, oncolytic adenoviruses for prostate cancer.

The first human clinical trial of a PSA-selective, replication-restricted, oncolytic adenovirus was conducted by Johns Hopkins SPORE Program investigators and reported in 2001.  In this trial, the cytolytic virus, genetically-engineered to use the PSA promoter/enhancer to replicate selectively in PSA-producing cells, was administered intraprostatically to men (n = 25) with local prostate cancer recurrences after initial radiation therapy.  The trial design featured a viral particle dose escalation, from 1 x 1011 to 1 x 1013, delivered via real-time, trans-rectal ultrasound-guided, trans-perineal injection.  The results were promising, with 5 of the men, from the highest two viral particle dose levels, showing serum PSA changes, and none of the men suffering unacceptable toxicity.  Nonetheless, the further development of this treatment approach as intravenous therapy for disseminated metastatic prostate cancer was temporarily halted in response to the well-publicized and tragic death of an adenovirus gene therapy clinical trial participant at the University of Pennsylvania.  However, the trial of PSA-selective, replication-restricted, cytolytic adenovirus therapy for metastatic prostate cancer was ultimately allowed to proceed, with support from a commercial partner, Cell Genesys.  In a multi-institutional phase 1 study involving a collaboration between two Prostate Cancer SPORE Programs, viral particles were aministered as a single intravenous infusions in dose escalation design, from 1 x 1010 to 6 x 1012 viral particles, to men (n = 23) with hormone-refractory metastatic prostate cancer.  Flu-like symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common side effects, with 3 treatment-associated grade 3 adverse events reported.  At doses greater than 1012 viral particles, all 5 of the men treated exhibited increased liver enzymes and/or D-dimer levels, terminating the dose escalation at 6 x 1012 viral particles.  Of interest, secondary elevations in circulating viral genome copy numbers, indicative of viral replication, were seen in 16 or the 23 men (70%) treated.  5 of the men, including 3 of 8 men treated at the highest dose levels, enjoyed declines in serum PSA values of 25-49%.  With this clinical experience, further translational research and development returned to the laboratory setting, as part of a Research Project supported during the last funding period, with renewed focus on molecular strategies for improving specificity for prostate cancer cells via redirecting viral tropism (eg. modifying the virus fiber knob to bind prostate-specific membrane antigen), and for augmenting viral lethality (eg. by incorporating new virus genes to antagonize prostate cancer cell growth and survival pathways).

(v) Somatic epigenetic changes as molecular biomarkers for prostate cancer.

The use of serum assays for PSA as a prostate cancer screening tool has dramatically changed the natural history of prostate cancer, and may be responsible, in part for the recent decline in prostate cancer mortalilty.  As a result of PSA screening, prostate cancer, which once first became evident when complicated by symptomatic metastases, now more typically presents as a localized tumor suitable for treatment by radical prostatectomy or with radiation therapy.  Nonetheless, PSA screening is far from perfect: in the Prostate Cancer Prevention Trial (PCPT), 24.4% of men on the placebo treatment arm who entered the study with “normal” serum PSA values and underwent prostate biopsies at the end of the trial were found to have prostate cancer.  The current approach to prostate biopsy for prostate cancer detection and diagnosis also leaves a lot to be desired: the typical ultrasound-guided biopsy strategy features random sampling of ~0.3% of prostate tissue, rather than biopsies targeted at some sort of radiographic image abnormality like for other cancers.  Also, controversies remains concerning the optimal number of tissue cores that should be obtained during a prostate biopsy procedure, and about which men should be subjected to repeat biopsy procedures if cancer is not detected.  Furthermore, because prostate cancers may be present in more than half of all men over age 50 years, yet threaten morbidity and/or mortality in only 5% or less of men, the wisdom of prostate cancer screening and early detection has been questioned  To confront these challenges, new molecular biomarkers have been sought that could be useful for prostate cancer prostate cancer screening, for improving the detection and diagnosis of localized prostate cancer, and for directing treatment choices for men with prostate cancer.

Somatic epigenetic alterations offer a great source of potential molecular biomarkers for prostate cancer and for other human cancers for several reasons: (i) somatic hypermethylation of CpG island sequences have been consistently associated with virtually all human cancers, including prostate cancers, (ii) CpG island methylation can be readily detected in genomic DNA using very sensitive and specific polymerase chain reaction (PCR) strategies, (iii) genomic DNA may be superior to RNA, protein, and other macromolecules in terms of stability for biospecimen collection and handling, and (iv) CpG island methylation changes appear to be more consistently present in different cancer cases, particularly in different prostate cancer cases, than somatic genetic changes, such as mutations, deletions, and translocations, permitting one or a few assays to be used as a test.

There are now three major strategies for the detection of CpG dinucleotide methylation changes in genomic DNA from cancer cells.  The first approach features the use of restriction endonucleases that cut recognition sites differently if the sites contain 5-meCpG.  Such enzymes have been used along with Southern blot analysis and with PCR to discriminate DNA methylation changes at particular genome sites.  Assays using 5-meCpG-sensitive restriction enzymes and PCR (RE-PCR) have proven spectacularly sensitive, capable of detecting single hypermethylated CpG island sequences, but appear prone to false-positive results, arising from incomplete cutting of unmethylated sequences and insufficient suppression of PCR amplification of unmethylated CpG island alleles.  The second strategy, developed for biomarker detection by Drs. James G. Herman and Stephen B. Baylin of the Johns Hopkins Lung Cancer SPORE Program, uses sodium bisulfite modification to facilitate the selective deamination of C, but not of 5-meC, to U, creating a DNA sequence difference at C versus 5-meC after PCR amplification.  This approach has been used for mapping and sequencing of 5-meC at specific genome sites, and serves as the basis for a PCR assay in which primers specific for bisulfite/deamination converted sequences containing 5-meC versus C are used to detect hypermethylated CpG islands.  The bisulfite modification and PCR (MS-PCR) assays, though often quite specific, can be less sensitive than RE-PCR assays because the bisulfite modification procedure can damage target DNA sequences.  A third approach involves selective capture of 5-meC-containing sequences with 5-meC-binding proteins or anti-5-meC antibodies.  COMPARE-MS, a new assays that features capture of 5-meC-containing DNA has been developed for use by Drs. Srinivasan Yegnasubramanian and William G. Nelson in a Research Project Proposed as part of the current Prostate Cancer SPORE competitive renewal application.  

Epigenetic silencing of GSTP1, encoding the p-class glutathione S-transferase (GST), is nearly ubiquitously associated with prostate cancer, a discovery first made by Dr. William G. Nelson and colleagues in pursuit of a SPORE Research Project.  The CpG island encompassing the GSTP1 transcriptional promoter is devoid of 5-meC in normal cells of the prostate and other tissues, but in almost all prostate cancers that have been carefully studied, the GSTP1 CpG island is densely methylated and the gene is transcriptionally silent.  Several different detection strategies have been used to detect GSTP1 CpG island hypermethylation: in a recent review of some 24 published studies with 1071 prostate cancer cases, GSTP1 CpG island hypermethylation was found in prostate cancer DNA from more than 81% of the cases analyzed.  The sensitivity of assays for GSTP1 CpG hypermethylation varied substantially depending on the assay strategy used and the specific region of the GSTP1 CpG island targeted  Using COMPARE-MS, one of the new 5-meC-containing DNA capture assays, GSTP1 CpG island hypermethylation exhibited 99.2% sensitivity and 100% specificity for DNA from prostate cancer versus normal prostate tissue.  For this reason, several different GSTP1 CpG island hypermethylation assays are under clinical development as tools for prostate cancer detection and diagnosis by Veridex, L.L.C., another example of a “hand-off” of SPORE technology for commercial development.  Using GSTP1 CpG island hypermethylation as a molecular biomarker of prostate cancer, prostate cancer cells, or cell-free prostate cancer DNA, has been detected in prostate tissue biopsies, in prostate secretions or in the urine, and in the circulation.

(vi) Endothelin-1 receptor antagonists for prostate cancer.

Advanced prostate cancer that has metastasized to bones, producing osteoblastic lesions, often causes intense bone pain that is difficult to control.  New drugs are needed to interrupt the process of prostate cancer metastasis to bone.  Studies carried out as part of the Prostate Cancer SPORE Program under the direction of Dr. Jonathan W. Simons and his Postdoctoral Fellow, Dr. Joel B. Nelson, indicated that endothelin-1 might be involved in mediating prostate cancer morbidity by contributing to bone pain associated with prostate cancer metastasis.  Extensive preclinical work, conducted by Dr. Nelson, indicated the feasibility of using endothelin-1 receptor-A (ETr-A) antagonists in this capacity.  Preclinical studies suggested that ETr-A antagonists might interfere with the progression of the prostate cancer metastasis to bone.  In conjunction with Abbot Laboratories, Dr. Nelson and SPORE Program Investigator Dr. Michael A. Carducci directed a series of clinical trials of an orally active ETr-A antagonist, atrasentan (ABT-627), targeting men with advanced prostate cancer.  Early hints of clinical activity were documented in the initial phase 1 trials, as evidenced by a decrease in cancer-related pain in 5 of 15 subjects and decreases in prostate-specific antigen levels in 5 of 11 subjects with androgen-independent prostate cancer. The potential efficacy of atrasentan was evaluated in a randomized, placebo-controlled, phase 2 trial enrolling men (n = 288) with asymptomatic, metastatic, androgen-independent prostate cancer.  The median time-to-progression (TTP) for men receiving 10 mg of atrasentan daily was twice that of the placebo group (155 versus 71 days; p = 0.002).  In a separate pharmacodynamic analysis of biological end points in this trial, changes in serum bone deposition markers, total alkaline phosphatase and bone alkaline phosphatase, and urinary bone resorption markers, N-telopeptides, C-telopeptides, and deoxypyridinoline, were assessed, with results hinting at a drug attenuation of prostate cancer-associated bone destruction.

To test the efficacy of atrasentan against metastatic, androgen-independent prostate cancer, a randomized, double-blinded, placebo-controlled pivotal phase 3 study (n = 809 men) was undertaken.  The trial results revealed that although atrasentan did not improve the time-to-progression for the whole group, the drug did appear to delay the time-to-progression of bony lesions.  An exploratory post hoc analysis further suggested that the subset of men in the trial with bone metastases may have enjoyed a greater benefit than the subset with metastases at other anatomic sites.  With these findings Abbott Laboratories sought FDA approval for atrasentin for men with metastatic prostate cancer and bone metastases, but were required to collect additional data in support of the main treatment indication.  Nonetheless, the development of atrasentan is a clear example of a concept carried from an initial laboratory observation into human clinical trials as a product of the Johns Hopkins Prostate Cancer SPORE Program.

(vii) Alpha-methylacyl-CoA racemase (AMACR) as an immunohistochemical marker for prostate cancer.

In an era where most prostate cancer diagnoses are made by PSA screening and sampling core needle biopsies of the prostate, prostate pathologists have been challenged to make more accurate and definitive diagnoses with less tissue than ever before.  In a spectacular example of rapidly translated research findings, immunohistochemical staining for to alpha-methylacyl-CoA racemase (AMACR), first reported to be over-expressed in prostate cancer via transcriptome profiling analyses done in by Johns Hopkins Prostate Cancer SPORE investigators Drs. William B. Isaacs and Jun Luo, and for p63, found to be a normal prostate basal epithelial cell marker by Dr. Angelo M. De Marzo, was evaluated as adjunctive tool for the histopathological diagnosis of prostate cancer via a collaborative venture involving several Prostate Cancer SPORE Program pathologists throughout the US.  This immunohistochemical staining approach has now been reduced to state-of-the-art clinical practice, widely adopted by surgical pathologists throughout the world for the diagnosis of prostate cancer by needle biopsy.

Progress Made So Far by Current Prostate Cancer SPORE Research Projects (to be Completed by Spring 2008):

Research Project #1.  Targeted Activation of Cytotoxic Prodrugs by Prostate-Specific Proteases.

Co-Principal Investigators: Samuel R. Denmeade, M.D., and John T. Isaacs, Ph.D.

Specific Aims: (1) To evaluate a series of thapsigargin (TG) prodrugs in vitro in order to select prodrugs for further drug development; (2) To define the lead prodrug based upon its in vivo antitumor efficacy against human prostate cancer xenografts; (3) To determine whether coupling the lead prodrug identified in Aim (2)  to a polyethylene glycol (PEG) macromolecular carrier enhances in vivo antitumor efficacy; (4) To identify an hK2 specific peptide substrate and use this substrates to develop an hK2-activated TG prodrug according to the strategy outlined in Aims (1-3).

Progress Highlights: The Project has succeeded in turning a potentially novel, but highly toxic drug, TG, into a prodrug form that becomes activated by a protease produced by prostate cancers and not by normal tissue, with the exception of the normal prostate gland.  This approach should yield a new effective therapy that targets prostate cancer cells while minimizing toxicity to normal tissues ready for testing in human clinical trials.  Key accomplishments were:

• Discovery of PSA substrates that were 10-fold better (on the basis of kcat/km ratio) than the original lead peptide HSSKLQ, with one of the substrates, SSKYQ, providing ~50-fold better hydrolysis by PSA when linked to L12ADT (to make the prodrug Mu-SSKYQ-L12ADT) then the previous best lead candidate Mu-HSSKLQ-L12ADT;
• Establishment of the efficacy of Mu-SSKYQ-L12ADT in inhibiting growth of the PSA-producing human prostate cancer xenografts at doses as low as  70 mg/kg when given daily;
• Production of a PSA-activated protoxin using bacterial proaerolysin that cured ~30% of immunodeficient mice carrying human prostate cancer xenografts with one dose, prompting licensing of this agent to Protox Therapeutics Inc., a company that completed the necessary preclinical efficacy studies and toxicologic studies in rat, dogs and monkey, for an Investigational New Drug application by the FDA, and initiated clinical trials for men with prostate cancer in March of 2006;

Research Project #2.  Restoration of Gene Function in Prostate Cancer by Reversal of “CpG Island” DNA Methylation and Modulation of Chromatin Structure.

Co-Principal Investigators: Michael A. Carducci, M.D., and James G. Herman, M.D.

Specific Aims: (1) To initiate clinical trials of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors; (2) To explore dose and schedule of DNMT inhibitors in vitro and in vivo, (3) To explore dose and schedule of HDAC inhibitors in vitro and in vivo, (4) To assess effects of DNMT inhibitors on patterns of gene expression using transcriptome profiling technologies; (5) To assess effects of HDAC inhibitors on patterns of gene expression using transcriptome profiling technologies; (6) To test selected candidate CpG island methylation biomarkers as prostate cancer prognostic tools.

Progress Highlights: Two clinical trials of HDAC inhibitors were successfully launched by Project investigators and have been accruing study subjects, including a phase 1 study of MS-275 in combination with isotretinoin for metastatic progressive cancer and a phase 1 study of the HDAC isotype-specific drug MGCD0103 given as three-times weekly oral dose for advanced solid tumors.  Other key accomplishments:

• Discovery that the synergistic killing of prostate cancer cells in vitro with combinations of DNMT and HDAC inhibitors did not occur in vivo, thought to be attributable to confounding effects of the agents on tumor neovasculature;
• Determination that there were marked differences between patterns of genes reactivated in different prostate cancer cells upon exposure to HDAC inhibitors, prompting the need for more refined approaches to pharmacodynamic endpoint biomarkers for the clinical development of these drugs;
• Identification of the c-MYC down-regulated gene1 (NDRG1), encoding a cytoplasmic 43-kDa protein that promotes cell differentiation and decreases metastasis, as reactivated in prostate cancer cells by treatment with DNMT and HDAC inhibitors;
• Ascertaining that hypermethylation of either ASC and/or CDH13 in prostate cancer tissues was associated with an odds ratio of prostate cancer recurrence after surgery of 5.0 (with 95% confidence interval of 1.4-18.2 and p = 0.014) as compared to tissues from cases without methylation of either of these genes. 

Research Project #3.  Oncolytic Adenoviral Gene Therapy for Prostate Cancer.

Co-Principal Investigators: Ronald Rodriguez, M.D., Ph.D., and Theodore L. DeWeese, M.D.

Specific Aims: (1) To evaluate the efficacy of oncolytic viral therapy for both androgen dependent and androgen independent prostate cancer through the use of E1A-AR fusion chimera; (2) To evaluate the radiation sensitization of inhibiting DNA double stranded break (dsb) repair protein kinases (DNA-PKcs, ATM, and ATR) in combination with oncolytic adenoviruses; (3) To interrogate available clinical trial results from early experiences with PSA-selective, replication-restricted, oncolytic adenoviruses for possible pre-clinical vector improvement.

Progress Highlights: Although clinical trials of PSA-selective, replication-restricted, oncolytic adenoviruses, given intraprostatically or intravenously, were completed with promising hints of potential efficacy, as antiviral immunity emerged, repeated treatment courses were not feasible.  Nonetheless, the delivery of siRNAs disrupting expression of DNA dsb repair kinases for selective radiosensitization remained an attractive therapeutic goal, prompting a new strategy using selective targeting aptamers for siRNA delivery to prostate cancer to be developed as a Research Project in the current competitive renewal application.  Key milestones and achievements:

• Construction and preclinical testing of prostate-specific E1A-AR fusion viral constructs, producing enhanced specificity of the viruses for infecting prostate cancer cells;
• Determination that the p21 regulates adenoviral replication;
• Successful targeting of DNA dsb repair kinases with siRNAs but failure to generate adenovirus constructs capable of expressing interfering RNAs during replication/cytolysis, prompting exploration of alternative strategies for siRNA delivery into prostate cancer cells;

Research Project #4.  Sulforaphane for Prostate Cancer Prevention.

Co-Principal Investigators: William G. Nelson, M.D., Ph.D., and H. Ballentine Carter, M.D.

Specific Aims: (1) To test the correlation between dietary consumption of isothiocyanates and prostate cancer risk in the Baltimore Longitudinal Study of Aging (BLSA) cohort; (2) To determine whether broccoli sprouts extracts protect against mutagenesis and carcinogenesis in the rat ventral prostate caused by ingestion of the “charred meat” carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); (3) To introduce carcinogen-detoxification enzyme inducers into “proof-of-principle” clinical trials as candidate prevention agents.

Progress Highlights:  Although specimen storage problems precluded the epidemiological study of urinary isothiocyanate metabolites and prostate cancer risk, preclinical studies of PhIP-driven carcinogenesis and its prevention by broccoli sprouts extracts were feasible, informative, and provided the rationale for a “proof-of-principle” clinical study, supported using discretionary funds, of sulforaphane given to men with prostate cancer before radical prostatectomy.  In the trial, the isothiocyanate was detected in prostate tissues after oral ingestion.  Further development of this prostate cancer prevention strategy in clinical trials is anticipated.  Key findings from preclinical studies:

• Determination that PhIP consumption causes mutations in genomic DNA in sex accessory tissues, including ventral prostate, dorsolateral prostate, and seminal vesicles, out of proportion to proliferation rate (i.e. these tissues aggressively bioactivate PhIP to a DNA-damaging species);
• Discovery that cell and tissue damage in response to PhIP intake was confined to the ventral prostate, the major organ for neoplastic transformation;
• Observation that PhIP induced an inflammatory response, resulting in the recruitment of mast cells and macrophages, selectively in the ventral prostate.

Research Project #5.  DNA Polymorphisms in Genes Affecting Levels of Oxidative Stress in Prostate Cells: Population Studies of Association with Prostate Cancer Risk.

Co-Principal Investigators: William B. Isaacs, Ph.D., and Bruce J. Trock, Ph.D

Specific Aims: (1) To assemble collections of candidate genes, from oxidative damage/repair and host inflammatory response pathways for examination in population studies of prostate cancer risk genes, (2) To conduct risk association studies of genes from Aim (1).

Progress Highlights: Significant associations were detected with common polymorphic variants of genes in both the oxidative damage/repair and host inflammatory response pathways.  Also, refinements in genotyping technologies permitted more general searches of genetic contributions to prostate cancer risk, necessitating more significant collaboration and cross-population cohort validation efforts.  Key developments”

• Using the ParAllele Inflammation SNP Chip, which assays 10,000 SNPs in 1,000 genes involved in inflammation and oxidative stress, to analyze study populations from both Johns Hopkins and from Sweden, 8 SNPs in 7 genes were found to have associations with prostate cancer at p < 0.001 in a collection of 200 cases and controls from the CAPS study in Sweden, while 6 of these 8 SNPs (5 genes: IL15RA, CRLF1, TRAF6, ITGA9, and IGF1R) exhibited similar associations at p < 0.05 in 200 cases and controls from Hopkins.
• Whole genome-wide association studies, using the Affymetrix 100K SNP chips in a collaborative study with TGen in Arizona, Wake Forest University, and Umea University in Sweden, scans of two independent cohorts, one with 500 cases and 500 controls and one with 500 aggressive cases versus 500 indolent cases, have been analyzed, yielding candidate loci of association for over 340 SNPs in the original list of 51 candidate genes (~7SNPs/gene). 
• New candidate hereditary prostate cancer family genes have been found, including ATBF1, P53AIP1, and a new locus at 8q.

Young Scientists Developed:

In addition to the translational research achievements of the Johns Hopkins Prostate Cancer SPORE Program, one of the most gratifying aspects of the SPORE Program has been the support and development of young investigators as they began their independent research programs.  Dr. Jonathan W. Simons, now the Chief Executive Officer of the Prostate Cancer Foundation, and Dr. William G. Nelson, now the Principal Investigator of the SPORE Program, were the first beneficiaries of SPORE Program Career Development support.  Dr. Joel B. Nelson, now Chairman of Urology at the University of Pittsburgh, Dr. Theodore L. DeWeese, now Chairman of Radiation Oncology at Johns Hopkins, Dr. Michael A. Carducci, now director of the Chemical Therapeutics Program at Johns Hopkins, Dr. Ronald Rodriguez, an Associate Professor of Urology, Dr. Angelo De Marzo, an Associate Professor of Pathology, Dr. Samuel R. Denmeade, an Associate Professor of Oncology, Dr. Elizabeth A. Platz, now Associate Professor of Epidemiology, Dr. Charles G. Drake, Assistant Professor of Oncology, and Dr. Alan K. Meeker, Assistant Professor of Pathology, all at Johns Hopkins, and Dr. Charles Foster, now an Assistant Professor at the Cleveland Clinic, additionally benefited from SPORE Career Development funding.  Two new faculty members, David M. Berman, M.D., Ph.D., an Assistant Professor of Pathology, and Moshe Yair Levy, M.D., an Assistant Professor of Oncology, are the current recipients of SPORE Program Career Development support.

Prostate Cancer Publications by Johns Hopkins Prostate Cancer SPORE and SKCCC Prostate Cancer Program Investigators Since Last Competitive Renewal in 2002:

The Prostate Cancer SPORE Program, SKCCC Core Grant support of the Prostate Cancer Program, and Patrick C. Walsh Prostate Cancer Research Fund have permitted the assembly of a remarkably well-integrated translational research team focused on improving prostate cancer screening, detection, diagnosis, prevention, and treatment.  As a consequence of this integration, prostate cancer researchers at Johns Hopkins have become even more effective at securing philanthropic investments and peer-reviewed grant support, and ever better postured to direct biological discoveries toward clinical impact.  The output of publications by the prostate cancer research enterprise since the last competitive renewal features basic, translational, and clinical research, all affected by NCI SPORE Program support of Core infrastructure for translational research as well as some of the translational research portfolio.

2002

1. Berndt SI, Carter HB, Landis PK, et al. Calcium intake and prostate cancer risk in a long-term aging study: the Baltimore Longitudinal Study of Aging. Urology 2002;60(6):1118-23.
2. Brooks JD, Goldberg MF, Nelson LA, Wu D, Nelson WG. Identification of potential prostate cancer preventive agents through induction of quinone reductase in vitro. Cancer Epidemiol Biomarkers Prev 2002;11(9):868-75.
3. Carducci MA, Nelson JB, Bowling MK, et al. Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol 2002;20(8):2171-80.
4. Carpten J, Nupponen N, Isaacs S, et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature genetics 2002;30(2):181-4.
5. Carter HB, Walsh PC, Landis P, Epstein JI. Expectant management of nonpalpable prostate cancer with curative intent: preliminary results. The Journal of urology 2002;167(3):1231-4.
6. Chang BL, Zheng SL, Hawkins GA, et al. Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. Human genetics 2002;110(2):122-9.
7. Chang BL, Zheng SL, Hawkins GA, et al. Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility. Cancer research 2002;62(6):1784-9.
8. Chesire DR, Ewing CM, Gage WR, Isaacs WB. In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene 2002;21(17):2679-94.
9. Chesire DR, Isaacs WB. Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene 2002;21(55):8453-69.
10. De Marzo AM, Fedor HH, Gage WR, Rubin MA. Inadequate formalin fixation decreases reliability of p27 immunohistochemical staining: probing optimal fixation time using high-density tissue microarrays. Human pathology 2002;33(7):756-60.
11. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nature reviews 2002;2(5):389-96.
12. Ellison L, Cheli CD, Bright S, Veltri RW, Partin AW. Cost-benefit analysis of total, free/total, and complexed prostate-specific antigen for prostate cancer screening. Urology 2002;60(4 Suppl 1):42-6.
13. Fang J, Metter EJ, Landis P, Carter HB. PSA velocity for assessing prostate cancer risk in men with PSA levels between 2.0 and 4.0 ng/ml. Urology 2002;59(6):889-93; discussion 93-4.
14. Fichtinger G, DeWeese TL, Patriciu A, et al. System for robotically assisted prostate biopsy and therapy with intraoperative CT guidance. Academic radiology 2002;9(1):60-74.
15. Gillespie JW, Best CJ, Bichsel VE, et al. Evaluation of non-formalin tissue fixation for molecular profiling studies. The American journal of pathology 2002;160(2):449-57.
16. Gretzer MB, Epstein JI, Pound CR, Walsh PC, Partin AW. Substratification of stage T1C prostate cancer based on the probability of biochemical recurrence. Urology 2002;60(6):1034-9.
17. Gretzer MB, Trock BJ, Han M, Walsh PC. A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria. The Journal of urology 2002;168(4 Pt 1):1419-22.
18. Haese A, Dworschack RT, Partin AW. Percent free prostate specific antigen in the total prostate specific antigen 2 to 4 ng./ml. range does not substantially increase the number of biopsies needed to detect clinically significant prostate cancer compared to the 4 to 10 ng./ml. range. The Journal of urology 2002;168(2):504-8.
19. Haese A, Dworschack RT, Piccoli SP, Sokoll LJ, Partin AW, Chan DW. Clinical evaluation of the Elecsys total prostate-specific antigen assay on the Elecsys 1010 and 2010 systems. Clinical chemistry 2002;48(6 Pt 1):944-7.
20. Haese A, Epstein JI, Huland H, Partin AW. Validation of a biopsy-based pathologic algorithm for predicting lymph node metastases in patients with clinically localized prostate carcinoma. Cancer 2002;95(5):1016-21.
21. Hawkins GA, Cramer SD, Zheng SL, et al. Sequence variants in the human 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27B1) gene are not associated with prostate cancer risk. The Prostate 2002;53(3):175-8.
22. Hawkins GA, Mychaleckyj JC, Zheng SL, et al. Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer genetics and cytogenetics 2002;137(1):1-7.
23. Heath EI, DeWeese TL, Partin AW, et al. The design of a randomized, placebo-controlled trial of celecoxib in preprostatectomy men with clinically localized adenocarcinoma of the prostate. Clinical prostate cancer 2002;1(3):182-7.
24. Ho GY, Knapp M, Freije D, et al. Transmission/disequilibrium tests of androgen receptor and glutathione S-transferase pi variants in prostate cancer families. International journal of cancer 2002;98(6):938-42.
25. Horninger W, Cheli CD, Babaian RJ, et al. Complexed prostate-specific antigen for early detection of prostate cancer in men with serum prostate-specific antigen levels of 2 to 4 nanograms per milliliter. Urology 2002;60(4 Suppl 1):31-5.
26. Isaacs W, De Marzo A, Nelson WG. Focus on prostate cancer. Cancer cell 2002;2(2):113-6.
27. Kibel AS, Faith DA, Bova GS, Isaacs WB. Mutational analysis of ETV6 in prostate carcinoma. The Prostate 2002;52(4):305-10.
28. Konety BR, Somogyi G, Atan A, Muindi J, Chancellor MB, Getzenberg RH. Evaluation of intraprostatic metabolism of 1,25-dihydroxyvitamin D(3) (calcitriol) using a microdialysis technique. Urology 2002;59(6):947-52.
29. Li Y, McCadden J, Ferrer F, et al. Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer. Cancer research 2002;62(9):2576-82.
30. Luo J, Zha S, Gage WR, et al. Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer. Cancer research 2002;62(8):2220-6.
31. Lupold SE, Hicke BJ, Lin Y, Coffey DS. Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer research 2002;62(14):4029-33.
32. Makarov DV, Sanderson H, Partin AW, Epstein JI. Gleason score 7 prostate cancer on needle biopsy: is the prognostic difference in Gleason scores 4 + 3 and 3 + 4 independent of the number of involved cores? The Journal of urology 2002;167(6):2440-2.
33. Meeker AK, Gage WR, Hicks JL, et al. Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. The American journal of pathology 2002;160(4):1259-68.
34. Meeker AK, Hicks JL, Platz EA, et al. Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer research 2002;62(22):6405-9.
35. Mhaka A, Denmeade SR, Yao W, Isaacs JT, Khan SR. A 5-fluorodeoxyuridine prodrug as targeted therapy for prostate cancer. Bioorganic & medicinal chemistry letters 2002;12(17):2459-61.
36. Mikolajczyk SD, Marks LS, Partin AW, Rittenhouse HG. Free prostate-specific antigen in serum is becoming more complex. Urology 2002;59(6):797-802.
37. Naya Y, Stamey TA, Cheli CD, et al. Can volume measurement of the prostate enhance the performance of complexed prostate-specific antigen? Urology 2002;60(4 Suppl 1):36-41.
38. Okihara K, Cheli CD, Partin AW, et al. Comparative analysis of complexed prostate specific antigen, free prostate specific antigen and their ratio in detecting prostate cancer. The Journal of urology 2002;167(5):2017-23; discussion 23-4.
39. Oliai BR, Kahane H, Epstein JI. Can basal cells be seen in adenocarcinoma of the prostate?: an immunohistochemical study using high molecular weight cytokeratin (clone 34betaE12) antibody. The American journal of surgical pathology 2002;26(9):1151-60.
40. O'Malley KJ, Pound CR, Walsh PC, Epstein JI, Partin AW. Influence of biopsy perineural invasion on long-term biochemical disease-free survival after radical prostatectomy. Urology 2002;59(1):85-90.
41. Pinski J, Weeraratna A, Uzgare AR, Arnold JT, Denmeade SR, Isaacs JT. Trk receptor inhibition induces apoptosis of proliferating but not quiescent human osteoblasts. Cancer research 2002;62(4):986-9.
42. Platz EA. Energy imbalance and prostate cancer. The Journal of nutrition 2002;132(11 Suppl):3471S-81S.
43. Platz EA, Helzlsouer KJ, Hoffman SC, Morris JS, Baskett CK, Comstock GW. Prediagnostic toenail cadmium and zinc and subsequent prostate cancer risk. The Prostate 2002;52(4):288-96.
44. Platz EA, Krithivas K, Kantoff PW, Stampfer MJ, Giovannucci E. ATAAA repeat upstream of glutathione S-transferase P1 and prostate cancer risk. Urology 2002;59(1):159-64.
45. Pomper MG, Musachio JL, Zhang J, et al. 11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol Imaging 2002;1(2):96-101.
46. Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer 2002;94(4):987-96.
47. Rioux-Leclercq NC, Chan DY, Epstein JI. Prediction of outcome after radical prostatectomy in men with organ-confined Gleason score 8 to 10 adenocarcinoma. Urology 2002;60(4):666-9.
48. Rioux-Leclercq NC, Epstein JI. Unusual morphologic patterns of basal cell hyperplasia of the prostate. The American journal of surgical pathology 2002;26(2):237-43.
49. Sinibaldi VJ, Carducci MA, Moore-Cooper S, Laufer M, Zahurak M, Eisenberger MA. Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma. Cancer 2002;94(5):1457-65.
50. Sokoll LJ, Bruzek DJ, Dua R, et al. Short-term stability of the molecular forms of prostate-specific antigen and effect on percent complexed prostate-specific antigen and percent free prostate-specific antigen. Urology 2002;60(4 Suppl 1):24-30.
51. Sokoll LJ, Mangold LA, Partin AW, et al. Complexed prostate-specific antigen as a staging tool for prostate cancer: a prospective study in 420 men. Urology 2002;60(4 Suppl 1):18-23.
52. Song DY, Thompson TL, Ramakrishnan V, et al. Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology 2002;60(2):281-7.
53. Srodon M, Epstein JI. Central zone histology of the prostate: a mimicker of high-grade prostatic intraepithelial neoplasia. Human pathology 2002;33(5):518-23.
54. Takaha N, Hawkins AL, Griffin CA, Isaacs WB, Coffey DS. High mobility group protein I(Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells. Cancer research 2002;62(3):647-51.
55. Taneja SS, Hsu EI, Cheli CD, et al. Complexed prostate-specific antigen as a staging tool: results based on a multicenter prospective evaluation of complexed prostate-specific antigen in cancer diagnosis. Urology 2002;60(4 Suppl 1):10-7.
56. Tombal B, Denmeade SR, Gillis JM, Isaacs JT. A supramicromolar elevation of intracellular free calcium ([Ca(2+)](i)) is consistently required to induce the execution phase of apoptosis. Cell death and differentiation 2002;9(5):561-73.
57. Veltri RW, Chaudhari M, Miller MC, Poole EC, O'Dowd GJ, Partin AW. Comparison of logistic regression and neural net modeling for prediction of prostate cancer pathologic stage. Clinical chemistry 2002;48(10):1828-34.
58. Veltri RW, Miller MC, Mangold LA, O'Dowd GJ, Epstein JI, Partin AW. Prediction of pathological stage in patients with clinical stage T1c prostate cancer: the new challenge. The Journal of urology 2002;168(1):100-4.
59. Veltri RW, Miller MC, O'Dowd G J, Partin AW. Impact of age on total and complexed prostate-specific antigen cutoffs in a contemporary referral series of men with prostate cancer. Urology 2002;60(4 Suppl 1):47-52.
60. Wians FH, Jr., Cheli CD, Balko JA, Bruzek DJ, Chan DW, Sokoll LJ. Evaluation of the clinical performance of equimolar- and skewed-response total prostate-specific antigen assays versus complexed and free PSA assays and their ratios in discriminating between benign prostatic hyperplasia and prostate cancer. Clinica chimica acta; international journal of clinical chemistry 2002;326(1-2):81-95.
61. Wright EJ, Fang J, Metter EJ, et al. Prostate specific antigen predicts the long-term risk of prostate enlargement: results from the Baltimore Longitudinal Study of Aging. The Journal of urology 2002;167(6):2484-7; discussion 7-8.
62. Xu J, Zheng SL, Komiya A, et al. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nature genetics 2002;32(2):321-5.
63. Xu J, Zheng SL, Turner A, et al. Associations between hOGG1 sequence variants and prostate cancer susceptibility. Cancer research 2002;62(8):2253-7.
64. Yang G, Ayala G, De Marzo A, et al. Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res 2002;8(11):3419-26.
65. Zheng SL, Chang BL, Faith DA, et al. Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk. Cancer research 2002;62(22):6485-8.

2003

66. Allan RW, Sanderson H, Epstein JI. Correlation of minute (0.5 MM or less) focus of prostate adenocarcinoma on needle biopsy with radical prostatectomy specimen: role of prostate specific antigen density. The Journal of urology 2003;170(2 Pt 1):370-2.
67. Allen EA, Brinker DA, Coppola D, Diaz JI, Epstein JI. Multilocular prostatic cystadenoma with high-grade prostatic intraepithelial neoplasia. Urology 2003;61(3):644.
68. Bhujwalla ZM, Artemov D, Natarajan K, Solaiyappan M, Kollars P, Kristjansen PE. Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470. Clin Cancer Res 2003;9(1):355-62.
69. Bouwman K, Qiu J, Zhou H, et al. Microarrays of tumor cell derived proteins uncover a distinct pattern of prostate cancer serum immunoreactivity. Proteomics 2003;3(11):2200-7.
70. Cannon GM, Jr., Walsh PC, Partin AW, Pound CR. Prostate-specific antigen doubling time in the identification of patients at risk for progression after treatment and biochemical recurrence for prostate cancer. Urology 2003;62 Suppl 1:2-8.
71. Carducci MA, Padley RJ, Breul J, et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003;21(4):679-89.
72. Carter HB. Informed consent for prostate-specific antigen screening. Urology 2003;61(1):13-4.
73. Chan TY, Mikolajczyk SD, Lecksell K, et al. Immunohistochemical staining of prostate cancer with monoclonal antibodies to the precursor of prostate-specific antigen. Urology 2003;62(1):177-81.
74. Chang BL, Zheng SL, Isaacs SD, et al. Polymorphisms in the CYP1B1 gene are associated with increased risk of prostate cancer. British journal of cancer 2003;89(8):1524-9.
75. Chang BL, Zheng SL, Isaacs SD, et al. Polymorphisms in the CYP1A1 gene are associated with prostate cancer risk. International journal of cancer 2003;106(3):375-8.
76. Chang BL, Zheng SL, Isaacs SD, et al. Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer. The Prostate 2003;56(1):37-44.
77. Chesire DR, Isaacs WB. Beta-catenin signaling in prostate cancer: an early perspective. Endocrine-related cancer 2003;10(4):537-60.
78. Collis SJ, Ketner GW, Hicks JL, Nelson WG, Demarzo AM, Deweese TL. Expression of the DNA-PK binding protein E4-34K fails to confer radiation sensitivity to mammalian cells. International journal of radiation biology 2003;79(1):53-60.
79. Collis SJ, Swartz MJ, Nelson WG, DeWeese TL. Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer research 2003;63(7):1550-4.
80. DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI. Pathological and molecular aspects of prostate cancer. Lancet 2003;361(9361):955-64.
81. Denmeade SR, Jakobsen CM, Janssen S, et al. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. Journal of the National Cancer Institute 2003;95(13):990-1000.
82. Denmeade SR, Litvinov I, Sokoll LJ, Lilja H, Isaacs JT. Prostate-specific antigen (PSA) protein does not affect growth of prostate cancer cells in vitro or prostate cancer xenografts in vivo. The Prostate 2003;56(1):45-53.
83. Denmeade SR, Sokoll LJ, Dalrymple S, et al. Dissociation between androgen responsiveness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. The Prostate 2003;54(4):249-57.
84. Gao AC, Lou W, Dong JT, Barrett JC, Danielpour D, Isaacs JT. Defining regulatory elements in the human KAI1 (CD 82) metastasis suppressor gene. The Prostate 2003;57(4):256-60.
85. Gonzalgo ML, Brotzman M, Trock BJ, Geringer AM, Burnett AL, Jarow JP. Clinical efficacy of sildenafil citrate and predictors of long-term response. The Journal of urology 2003;170(2 Pt 1):503-6.
86. Gonzalgo ML, Pavlovich CP, Lee SM, Nelson WG. Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res 2003;9(7):2673-7.
87. Haese A, Chaudhari M, Miller MC, et al. Quantitative biopsy pathology for the prediction of pathologically organ-confined prostate carcinoma: a multiinstitutional validation study. Cancer 2003;97(4):969-78.
88. Haese A, Vaisanen V, Finlay JA, et al. Standardization of two immunoassays for human glandular kallikrein 2. Clinical chemistry 2003;49(4):601-10.
89. Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI, Walsh PC. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. The Journal of urology 2003;169(2):517-23.
90. Harden SV, Guo Z, Epstein JI, Sidransky D. Quantitative GSTP1 methylation clearly distinguishes benign prostatic tissue and limited prostate adenocarcinoma. The Journal of urology 2003;169(3):1138-42.
91. Harden SV, Sanderson H, Goodman SN, et al. Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies. Journal of the National Cancer Institute 2003;95(21):1634-7.
92. Hlavaty JJ, Partin AW, Shue MJ, et al. Identification and preliminary clinical evaluation of a 50.8-kDa serum marker for prostate cancer. Urology 2003;61(6):1261-5.
93. Hsieh LJ, Carter HB, Landis PK, et al. Association of energy intake with prostate cancer in a long-term aging study: Baltimore Longitudinal Study of Aging (United States). Urology 2003;61(2):297-301.
94. Hughes MA, Wang A, DeWeese TL. Two secondary malignancies after radiotherapy for seminoma: case report and review of the literature. Urology 2003;62(4):748.
95. Kalra P, Togami J, Bansal BSG, et al. A neurocomputational model for prostate carcinoma detection. Cancer 2003;98(9):1849-54.
96. Kasai M, Guerrero-Santoro J, Friedman R, Leman ES, Getzenberg RH, DeFranco DB. The Group 3 LIM domain protein paxillin potentiates androgen receptor transactivation in prostate cancer cell lines. Cancer research 2003;63(16):4927-35.
97. Khan MA, Carducci MA, Partin AW. The evolving role of docetaxel in the management of androgen independent prostate cancer. The Journal of urology 2003;170(5):1709-16.
98. Khan MA, Carter HB, Epstein JI, et al. Can prostate specific antigen derivatives and pathological parameters predict significant change in expectant management criteria for prostate cancer? The Journal of urology 2003;170(6 Pt 1):2274-8.
99. Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Long-term cancer control of radical prostatectomy in men younger than 50 years of age: update 2003. Urology 2003;62(1):86-91; discussion -2.
100. Khan MA, Partin AW, Carter HB. Expectant management of localized prostate cancer. Urology 2003;62(5):793-9.
101. Khan MA, Partin AW, Mangold LA, Epstein JI, Walsh PC. Probability of biochemical recurrence by analysis of pathologic stage, Gleason score, and margin status for localized prostate cancer. Urology 2003;62(5):866-71.
102. Khan MA, Partin AW, Rittenhouse HG, et al. Evaluation of proprostate specific antigen for early detection of prostate cancer in men with a total prostate specific antigen range of 4.0 to 10.0 ng/ml. The Journal of urology 2003;170(3):723-6.
103. Khan MA, Walsh PC, Miller MC, et al. Quantitative alterations in nuclear structure predict prostate carcinoma distant metastasis and death in men with biochemical recurrence after radical prostatectomy. Cancer 2003;98(12):2583-91.
104. Kibel AS, Faith DA, Bova GS, Isaacs WB. Xq27-28 deletions in prostate carcinoma. Genes, chromosomes & cancer 2003;37(4):381-8.
105. Kronz JD, Milord R, Wilentz R, Weir EG, Schreiner SR, Epstein JI. Lesions missed on prostate biopsies in cases sent in for consultation. The Prostate 2003;54(4):310-4.
106. Kunz GM, Jr., Epstein JI. Should each core with prostate cancer be assigned a separate gleason score? Human pathology 2003;34(9):911-4.
107. Li S, Simons J, Detorie N, O'Rourke B, Hamper U, DeWeese TL. Dosimetric and technical considerations for interstitial adenoviral gene therapy as applied to prostate cancer. International journal of radiation oncology, biology, physics 2003;55(1):204-14.
108. Litvinov IV, De Marzo AM, Isaacs JT. Is the Achilles' heel for prostate cancer therapy a gain of function in androgen receptor signaling? The Journal of clinical endocrinology and metabolism 2003;88(7):2972-82.
109. Lowe FC, McConnell JD, Hudson PB, et al. Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia. Urology 2003;61(4):791-6.
110. Luo J, Dunn TA, Ewing CM, Walsh PC, Isaacs WB. Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma. The Prostate 2003;57(2):134-9.
111. Luo J, Isaacs WB, Trent JM, Duggan DJ. Looking beyond morphology: cancer gene expression profiling using DNA microarrays. Cancer investigation 2003;21(6):937-49.
112. Magi-Galluzzi C, Epstein JI. Threshold for diagnosing prostate cancer over time. Human pathology 2003;34(11):1116-8.
113. Magi-Galluzzi C, Luo J, Isaacs WB, Hicks JL, de Marzo AM, Epstein JI. Alpha-methylacyl-CoA racemase: a variably sensitive immunohistochemical marker for the diagnosis of small prostate cancer foci on needle biopsy. The American journal of surgical pathology 2003;27(8):1128-33.
114. Magi-Galluzzi C, Sanderson H, Epstein JI. Atypia in nonneoplastic prostate glands after radiotherapy for prostate cancer: duration of atypia and relation to type of radiotherapy. The American journal of surgical pathology 2003;27(2):206-12.
115. Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 2003;16(9):902-12.
116. Nakayama M, Bennett CJ, Hicks JL, et al. Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. The American journal of pathology 2003;163(3):923-33.
117. Naya Y, Fritsche HA, Cheli CD, et al. Volume indexes of total, free, and complexed prostate-specific antigen enhance prediction of extraprostatic disease extension in men with nonpalpable prostate cancer. Urology 2003;62(6):1058-62.
118. Nelson JB, Nabulsi AA, Vogelzang NJ, et al. Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. The Journal of urology 2003;169(3):1143-9.
119. Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. The New England journal of medicine 2003;349(4):366-81.
120. Park J, Sokoll LJ, Bruzek DJ, et al. Comparison of total prostate-specific antigen and derivative levels in a screening population of black, white, and Korean-American men. Clinical prostate cancer 2003;2(3):173-6.
121. Partin AW, Brawer MK, Bartsch G, et al. Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. The Journal of urology 2003;170(5):1787-91.
122. Platz EA, Leitzmann MF, Michaud DS, Willett WC, Giovannucci E. Interrelation of energy intake, body size, and physical activity with prostate cancer in a large prospective cohort study. Cancer research 2003;63(23):8542-8.
123. Presti JC, Jr., O'Dowd GJ, Miller MC, Mattu R, Veltri RW. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a community multi-practice study. The Journal of urology 2003;169(1):125-9.
124. Roberts WW, Platz EA, Walsh PC. Association of cigarette smoking with extraprostatic prostate cancer in young men. The Journal of urology 2003;169(2):512-6; discussion 6.
125. Rohrmann S, Roberts WW, Walsh PC, Platz EA. Family history of prostate cancer and obesity in relation to high-grade disease and extraprostatic extension in young men with prostate cancer. The Prostate 2003;55(2):140-6.
126. Ruggeri B, Singh J, Gingrich D, et al. CEP-7055: a novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models. Cancer research 2003;63(18):5978-91.
127. Sokoll LJ, Chan DW, Mikolajczyk SD, et al. Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis. Urology 2003;61(2):274-6.
128. van Leenders GJ, Gage WR, Hicks JL, et al. Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy. The American journal of pathology 2003;162(5):1529-37.
129. Xiang Y, Wang Z, Murakami J, et al. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. Cancer research 2003;63(20):6795-801.
130. Xu J, Gillanders EM, Isaacs SD, et al. Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families. The Prostate 2003;57(4):320-5.
131. Xu J, Zheng SL, Komiya A, et al. Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. American journal of human genetics 2003;72(1):208-12.
132. Zha S, Ferdinandusse S, Denis S, et al. Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer. Cancer research 2003;63(21):7365-76.
133. Zheng SL, Mychaleckyj JC, Hawkins GA, et al. Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study. Mutation research 2003;528(1-2):45-53.
134. Zhou M, Epstein JI. The reporting of prostate cancer on needle biopsy: prognostic and therapeutic implications and the utility of diagnostic markers. Pathology 2003;35(6):472-9.
135. Zhou M, Jiang Z, Epstein JI. Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer. The American journal of surgical pathology 2003;27(6):772-8.

2004

136. Allaf ME, Palapattu GS, Trock BJ, Carter HB, Walsh PC. Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. The Journal of urology 2004;172(5 Pt 1):1840-4.
137. Aydin H, Tsuzuki T, Hernandez D, Walsh PC, Partin AW, Epstein JI. Positive proximal (bladder neck) margin at radical prostatectomy confers greater risk of biochemical progression. Urology 2004;64(3):551-5.
138. Bastacky S, Cieply K, Sherer C, Dhir R, Epstein JI. Use of interphase fluorescence in situ hybridization in prostate needle biopsy specimens with isolated high-grade prostatic intraepithelial neoplasia as a predictor of prostate adenocarcinoma on follow-up biopsy. Human pathology 2004;35(3):281-9.
139. Bastian PJ, Mangold LA, Epstein JI, Partin AW. Characteristics of insignificant clinical T1c prostate tumors. A contemporary analysis. Cancer 2004;101(9):2001-5.
140. Bastian PJ, Nakayama M, De Marzo AM, Nelson WG. [GSTP1 CpG island hypermethylation as a molecular marker of prostate cancer]. Der Urologe Ausg 2004;43(5):573-9.
141. Berman DM, Desai N, Wang X, et al. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Developmental biology 2004;267(2):387-98.
142. Brown WM, Lange EM, Chen H, et al. Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci. British journal of cancer 2004;90(2):510-4.
143. Carter HB. Continued undertreatment of older men with localized prostate cancer. Urology 2004;64(1):189-90; author reply 90.
144. Carter HB. Prostate cancers in men with low PSA levels--must we find them? The New England journal of medicine 2004;350(22):2292-4.
145. Carter HB, Isaacs WB. Improved biomarkers for prostate cancer: a definite need. Journal of the National Cancer Institute 2004;96(11):813-5.
146. Carter HB, Metter EJ, Wright J, Landis P, Platz E, Walsh PC. Prostate-specific antigen and all-cause mortality: results from the Baltimore Longitudinal Study On Aging. Journal of the National Cancer Institute 2004;96(7):557-8.
147. Chang BL, Zheng SL, Isaacs SD, et al. A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer. Cancer research 2004;64(6):1997-9.
148. Chesire DR, Dunn TA, Ewing CM, Luo J, Isaacs WB. Identification of aryl hydrocarbon receptor as a putative Wnt/beta-catenin pathway target gene in prostate cancer cells. Cancer research 2004;64(7):2523-33.
149. Coffey DS. A conversation between Darracott Vaughan and Donald S. Coffey. BJU international 2004;94(6):753-4.
150. Collis SJ, Schwaninger JM, Ntambi AJ, et al. Evasion of early cellular response mechanisms following low level radiation-induced DNA damage. The Journal of biological chemistry 2004;279(48):49624-32.
151. DeWeese TL. Radiation therapy and androgen suppression as treatment for clinically localized prostate cancer: the new standard? Jama 2004;292(7):864-6.
152. Eisenberger MA, Laufer M, Vogelzang NJ, et al. Phase I and clinical pharmacology of a type I and II, 5-alpha-reductase inhibitor (LY320236) in prostate cancer: elevation of estradiol as possible mechanism of action. Urology 2004;63(1):114-9.
153. Epstein JI. Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy. Mod Pathol 2004;17(3):307-15.
154. Faith DA, Isaacs WB, Morgan JD, et al. Trefoil factor 3 overexpression in prostatic carcinoma: prognostic importance using tissue microarrays. The Prostate 2004;61(3):215-27.
155. Farinola MA, Epstein JI. Utility of immunohistochemistry for alpha-methylacyl-CoA racemase in distinguishing atrophic prostate cancer from benign atrophy. Human pathology 2004;35(10):1272-8.
156. Freedland SJ, Mangold LA, Epstein JI, Partin AW. Biopsy indication--a predictor of pathologic stage among men with preoperative serum PSA levels of 4.0 ng/mL or less and T1c disease. Urology 2004;63(5):887-91.
157. Freedland SJ, Partin AW, Epstein JI, Walsh PC. Biochemical failure after radical prostatectomy in men with pathologic organ-confined disease: pT2a versus pT2b. Cancer 2004;100(8):1646-9.
158. Friedrichsen DM, Stanford JL, Isaacs SD, et al. Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families. Proceedings of the National Academy of Sciences of the United States of America 2004;101(7):1939-44.
159. Gillanders EM, Xu J, Chang BL, et al. Combined genome-wide scan for prostate cancer susceptibility genes. Journal of the National Cancer Institute 2004;96(16):1240-7.
160. Gonzalgo ML, Nakayama M, Lee SM, De Marzo AM, Nelson WG. Detection of GSTP1 methylation in prostatic secretions using combinatorial MSP analysis. Urology 2004;63(2):414-8.
161. Gretzer MB, Chan DW, van Rootselaar CL, et al. Proteomic analysis of dunning prostate cancer cell lines with variable metastatic potential using SELDI-TOF. The Prostate 2004;60(4):325-31.
162. Halushka MK, Kahane H, Epstein JI. Negative 34betaE12 staining in a small focus of atypical glands on prostate needle biopsy: a follow-up study of 332 cases. Human pathology 2004;35(1):43-6.
163. Han M, Partin AW, Chan DY, Walsh PC. An evaluation of the decreasing incidence of positive surgical margins in a large retropubic prostatectomy series. The Journal of urology 2004;171(1):23-6.
164. Hawkins GA, Chang BL, Zheng SL, et al. Mutational analysis of PINX1 in hereditary prostate cancer. The Prostate 2004;60(4):298-302.
165. Hubbard JS, Rohrmann S, Landis PK, et al. Association of prostate cancer risk with insulin, glucose, and anthropometry in the Baltimore longitudinal study of aging. Urology 2004;63(2):253-8.
166. Isaacs JT, Isaacs WB. Androgen receptor outwits prostate cancer drugs. Nature medicine 2004;10(1):26-7.
167. Janssen S, Jakobsen CM, Rosen DM, et al. Screening a combinatorial peptide library to develop a human glandular kallikrein 2-activated prodrug as targeted therapy for prostate cancer. Molecular cancer therapeutics 2004;3(11):1439-50.
168. Kakehi Y, Segawa T, Wu XX, Kulkarni P, Dhir R, Getzenberg RH. Down-regulation of macrophage inhibitory cytokine-1/prostate derived factor in benign prostatic hyperplasia. The Prostate 2004;59(4):351-6.
169. Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431(7009):707-12.
170. Kelloff GJ, Bast RC, Jr., Coffey DS, et al. Biomarkers, surrogate end points, and the acceleration of drug development for cancer prevention and treatment: an update prologue. Clin Cancer Res 2004;10(11):3881-4.
171. Kelloff GJ, Coffey DS, Chabner BA, et al. Prostate-specific antigen doubling time as a surrogate marker for evaluation of oncologic drugs to treat prostate cancer. Clin Cancer Res 2004;10(11):3927-33.
172. Khan MA, Carducci MA, Partin AW. Docetaxel in androgen-independent prostate cancer: an update. BJU international 2004;94(9):1209-10.
173. Khan MA, Mangold LA, Epstein JI, Boitnott JK, Walsh PC, Partin AW. Impact of surgical delay on long-term cancer control for clinically localized prostate cancer. The Journal of urology 2004;172(5 Pt 1):1835-9.
174. Khan MA, Sokoll LJ, Chan DW, et al. Clinical utility of proPSA and "benign" PSA when percent free PSA is less than 15%. Urology 2004;64(6):1160-4.
175. Kibel AS, Huagen J, Guo C, et al. Expression mapping at 12p12-13 in advanced prostate carcinoma. International journal of cancer 2004;109(5):668-72.
176. Lapidus RG, Dang W, Rosen DM, et al. Anti-tumor effect of combination therapy with intratumoral controlled-release paclitaxel (PACLIMER microspheres) and radiation. The Prostate 2004;58(3):291-8.
177. Lapointe J, Li C, Higgins JP, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 2004;101(3):811-6.
178. Leitzmann MF, Platz EA, Stampfer MJ, Willett WC, Giovannucci E. Ejaculation frequency and subsequent risk of prostate cancer. Jama 2004;291(13):1578-86.
179. Li J, White N, Zhang Z, et al. Detection of prostate cancer using serum proteomics pattern in a histologically confirmed population. The Journal of urology 2004;171(5):1782-7.
180. Lin KS, Luu A, Baidoo KE, et al. A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier. Bioconjugate chemistry 2004;15(6):1416-23.
181. Litvinov IV, Antony L, Isaacs JT. Molecular characterization of an improved vector for evaluation of the tumor suppressor versus oncogene abilities of the androgen receptor. The Prostate 2004;61(4):299-304.
182. Lupold SE, Rodriguez R. Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen. Molecular cancer therapeutics 2004;3(5):597-603.
183. Marks LS, Kojima M, Demarzo A, et al. Prostate cancer in native Japanese and Japanese-American men: effects of dietary differences on prostatic tissue. Urology 2004;64(4):765-71.
184. Meeker AK, Hicks JL, Iacobuzio-Donahue CA, et al. Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin Cancer Res 2004;10(10):3317-26.
185. Mhaka A, Gady AM, Rosen DM, Lo KM, Gillies SD, Denmeade SR. Use of methotrexate-based peptide substrates to characterize the substrate specificity of prostate-specific membrane antigen (PSMA). Cancer biology & therapy 2004;3(6):551-8.
186. Ong AM, Su LM, Varkarakis I, et al. Nerve sparing radical prostatectomy: effects of hemostatic energy sources on the recovery of cavernous nerve function in a canine model. The Journal of urology 2004;172(4 Pt 1):1318-22.
187. Palapattu GS, Allaf ME, Trock BJ, Epstein JI, Walsh PC. Prostate specific antigen progression in men with lymph node metastases following radical prostatectomy: results of long-term followup. The Journal of urology 2004;172(5 Pt 1):1860-4.
188. Parsons JK, Brawer MK, Cheli CD, Partin AW, Djavan R. Complexed prostate specific antigen (PSA) reduces unnecessary prostate biopsies in the 2.6-4.0 ng/mL range of total PSA. BJU international 2004;94(1):47-50.
189. Parsons JK, Marschke P, Maples P, Walsh PC. Effect of methylprednisolone on return of sexual function after nerve-sparing radical retropubic prostatectomy. Urology 2004;64(5):987-90.
190. Parsons JK, Partin AW. Applying complexed prostate-specific antigen to clinical practice. Urology 2004;63(5):815-8.
191. Parwani AV, Kronz JD, Genega EM, Gaudin P, Chang S, Epstein JI. Prostate carcinoma with squamous differentiation: an analysis of 33 cases. The American journal of surgical pathology 2004;28(5):651-7.
192. Platz EA, De Marzo AM, Erlinger TP, et al. No association between pre-diagnostic plasma C-reactive protein concentration and subsequent prostate cancer. The Prostate 2004;59(4):393-400.
193. Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E. Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control 2004;15(3):255-65.
194. Platz EA, Leitzmann MF, Rimm EB, Willett WC, Giovannucci E. Alcohol intake, drinking patterns, and risk of prostate cancer in a large prospective cohort study. American journal of epidemiology 2004;159(5):444-53.
195. Qian DZ, Wang X, Kachhap SK, et al. The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer research 2004;64(18):6626-34.
196. Rogers CG, Khan MA, Craig Miller M, Veltri RW, Partin AW. Natural history of disease progression in patients who fail to achieve an undetectable prostate-specific antigen level after undergoing radical prostatectomy. Cancer 2004;101(11):2549-56.
197. Rogers CG, Trock BP, Walsh PC. Preservation of accessory pudendal arteries during radical retropubic prostatectomy: surgical technique and results. Urology 2004;64(1):148-51.
198. Rogers CG, Yan G, Zha S, et al. Prostate cancer detection on urinalysis for alpha methylacyl coenzyme a racemase protein. The Journal of urology 2004;172(4 Pt 1):1501-3.
199. Schaeffer EM, Walsh PC. Risks of testosterone replacement. The New England journal of medicine 2004;350(19):2004-6; author reply -6.
200. Scheffel U, Pomper MG. PET imaging of GRP receptor expression in prostate cancer. J Nucl Med 2004;45(8):1277-8.
201. Scher HI, Eisenberger M, D'Amico AV, et al. Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 2004;22(3):537-56.
202. Sun J, Hedelin M, Zheng SL, et al. Interleukin-6 sequence variants are not associated with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2004;13(10):1677-9.
203. Takaha N, Resar LM, Vindivich D, Coffey DS. High mobility group protein HMGI(Y) enhances tumor cell growth, invasion, and matrix metalloproteinase-2 expression in prostate cancer cells. The Prostate 2004;60(2):160-7.
204. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. The New England journal of medicine 2004;351(15):1502-12.
205. Truskinovsky AM, Sanderson H, Epstein JI. Characterization of minute adenocarcinomas of prostate at radical prostatectomy. Urology 2004;64(4):733-7.
206. Uzgare AR, Isaacs JT. Enhanced redundancy in Akt and mitogen-activated protein kinase-induced survival of malignant versus normal prostate epithelial cells. Cancer research 2004;64(17):6190-9.
207. Uzgare AR, Xu Y, Isaacs JT. In vitro culturing and characteristics of transit amplifying epithelial cells from human prostate tissue. Journal of cellular biochemistry 2004;91(1):196-205.
208. Veltri RW, Khan MA, Miller MC, et al. Ability to predict metastasis based on pathology findings and alterations in nuclear structure of normal-appearing and cancer peripheral zone epithelium in the prostate. Clin Cancer Res 2004;10(10):3465-73.
209. Veltri RW, Park J, Miller MC, et al. Stromal-epithelial measurements of prostate cancer in native Japanese and Japanese-American men. Prostate Cancer Prostatic Dis 2004;7(3):232-7.
210. Wu K, Erdman JW, Jr., Schwartz SJ, et al. Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2004;13(2):260-9.
211. Xu J, Langefeld CD, Zheng SL, et al. Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage. Human genetics 2004;115(3):255-62.
212. Yegnasubramanian S, Kowalski J, Gonzalgo ML, et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer research 2004;64(6):1975-86.
213. Zheng SL, Augustsson-Balter K, Chang B, et al. Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer research 2004;64(8):2918-22.
214. Zhong H, Semenza GL, Simons JW, De Marzo AM. Up-regulation of hypoxia-inducible factor 1alpha is an early event in prostate carcinogenesis. Cancer detection and prevention 2004;28(2):88-93.
215. Zhou M, Aydin H, Kanane H, Epstein JI. How often does alpha-methylacyl-CoA-racemase contribute to resolving an atypical diagnosis on prostate needle biopsy beyond that provided by basal cell markers? The American journal of surgical pathology 2004;28(2):239-43.
216. Zhou M, Tokumaru Y, Sidransky D, Epstein JI. Quantitative GSTP1 methylation levels correlate with Gleason grade and tumor volume in prostate needle biopsies. The Journal of urology 2004;171(6 Pt 1):2195-8.

2005

217. Ali TZ, Epstein JI. Perineural involvement by benign prostatic glands on needle biopsy. The American journal of surgical pathology 2005;29(9):1159-63.
218. Aydin H, Zhou M, Herawi M, Epstein JI. Number and location of nucleoli and presence of apoptotic bodies in diagnostically challenging cases of prostate adenocarcinoma on needle biopsy. Human pathology 2005;36(11):1172-7.
219. Baffoe-Bonnie AB, Smith JR, Stephan DA, et al. A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region. Human genetics 2005;117(4):307-16.
220. Bastian PJ, Palapattu GS, Lin X, et al. Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following radical prostatectomy. Clin Cancer Res 2005;11(11):4037-43.
221. Berndt SI, Carter HB, Landis PK, et al. Prediagnostic plasma vitamin C levels and the subsequent risk of prostate cancer. Nutrition (Burbank, Los Angeles County, Calif 2005;21(6):686-90.
222. Burnett AL, Kramer MF, Dalrymple S, Isaacs JT. Nonimmunosuppressant immunophilin ligand GPI-1046 does not promote in vitro growth of prostate cancer cells. Urology 2005;65(5):1003-7.
223. Cao D, Hafez M, Berg K, Murphy K, Epstein JI. Little or no residual prostate cancer at radical prostatectomy: vanishing cancer or switched specimen?: a microsatellite analysis of specimen identity. The American journal of surgical pathology 2005;29(4):467-73.
224. Chang BL, Gillanders EM, Isaacs SD, et al. Evidence for a general cancer susceptibility locus at 3p24 in families with hereditary prostate cancer. Cancer letters 2005;219(2):177-82.
225. Chang BL, Isaacs SD, Wiley KE, et al. Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease. The Prostate 2005;64(4):356-61.
226. Collis SJ, DeWeese TL, Jeggo PA, Parker AR. The life and death of DNA-PK. Oncogene 2005;24(6):949-61.
227. Dalrymple S, Antony L, Xu Y, et al. Role of notch-1 and E-cadherin in the differential response to calcium in culturing normal versus malignant prostate cells. Cancer research 2005;65(20):9269-79.
228. Denmeade SR, Isaacs JT. The SERCA pump as a therapeutic target: making a "smart bomb" for prostate cancer. Cancer biology & therapy 2005;4(1):14-22.
229. DeWeese TL, Song DY. Radiation dose escalation as treatment for clinically localized prostate cancer: is more really better? Jama 2005;294(10):1274-6.
230. Drake CG, Doody AD, Mihalyo MA, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer cell 2005;7(3):239-49.
231. Egevad L, Allsbrook WC, Jr., Epstein JI. Current practice of Gleason grading among genitourinary pathologists. Human pathology 2005;36(1):5-9.
232. Ellison LM, Trock BJ, Poe NR, Partin AW. The effect of hospital volume on cancer control after radical prostatectomy. The Journal of urology 2005;173(6):2094-8.
233. Epstein JI, Sanderson H, Carter HB, Scharfstein DO. Utility of saturation biopsy to predict insignificant cancer at radical prostatectomy. Urology 2005;66(2):356-60.
234. Faith D, Han S, Lee DK, et al. p16 Is upregulated in proliferative inflammatory atrophy of the prostate. The Prostate 2005;65(1):73-82.
235. Fine SW, Epstein JI. Minute foci of Gleason score 8-10 on prostatic needle biopsy: a morphologic analysis. The American journal of surgical pathology 2005;29(7):962-8.
236. Foss CA, Mease RC, Fan H, et al. Radiolabeled small-molecule ligands for prostate-specific membrane antigen: in vivo imaging in experimental models of prostate cancer. Clin Cancer Res 2005;11(11):4022-8.
237. Freedland SJ, Grubb KA, Yiu SK, et al. Obesity and risk of biochemical progression following radical prostatectomy at a tertiary care referral center. The Journal of urology 2005;174(3):919-22.
238. Freedland SJ, Grubb KA, Yiu SK, et al. Obesity and capsular incision at the time of open retropubic radical prostatectomy. The Journal of urology 2005;174(5):1798-801; discussion 801.
239. Freedland SJ, Haffner MC, Landis PK, Saigal CS, Carter HB. Obesity does not adversely affect health-related quality-of-life outcomes after anatomic retropubic radical prostatectomy. Urology 2005;65(6):1131-6.
240. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. Jama 2005;294(4):433-9.
241. Freedland SJ, Isaacs WB. Explaining racial differences in prostate cancer in the United States: sociology or biology? The Prostate 2005;62(3):243-52.
242. Freedland SJ, Isaacs WB, Mangold LA, et al. Stronger association between obesity and biochemical progression after radical prostatectomy among men treated in the last 10 years. Clin Cancer Res 2005;11(8):2883-8.
243. Freedland SJ, Isaacs WB, Platz EA, et al. Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study. J Clin Oncol 2005;23(30):7546-54.
244. Freedland SJ, Mangold LA, Walsh PC, Partin AW. The prostatic specific antigen era is alive and well: prostatic specific antigen and biochemical progression following radical prostatectomy. The Journal of urology 2005;174(4 Pt 1):1276-81; discussion 81; author reply 81.
245. Freedland SJ, Sokoll LJ, Mangold LA, et al. Serum leptin and pathological findings at the time of radical prostatectomy. The Journal of urology 2005;173(3):773-6.
246. Freedland SJ, Sokoll LJ, Platz EA, et al. Association between serum adiponectin, and pathological stage and grade in men undergoing radical prostatectomy. The Journal of urology 2005;174(4 Pt 1):1266-70.
247. Freedland SJ, Terris MK, Platz EA, Presti JC, Jr. Body mass index as a predictor of prostate cancer: development versus detection on biopsy. Urology 2005;66(1):108-13.
248. Gonzalgo ML, Pavlovich CP, Trock BJ, Link RE, Sullivan W, Su LM. Classification and trends of perioperative morbidities following laparoscopic radical prostatectomy. The Journal of urology 2005;174(1):135-9; discussion 9.
249. Haese A, Vaisanen V, Lilja H, et al. Comparison of predictive accuracy for pathologically organ confined clinical stage T1c prostate cancer using human glandular kallikrein 2 and prostate specific antigen combined with clinical stage and Gleason grade. The Journal of urology 2005;173(3):752-6.
250. Haffner MC, Landis PK, Saigal CS, Carter HB, Freedland SJ. Health-related quality-of-life outcomes after anatomic retropubic radical prostatectomy in the phosphodiesterase type 5 ERA: impact of neurovascular bundle preservation. Urology 2005;66(2):371-6.
251. Heath EI, Gaskins M, Pitot HC, et al. A phase II trial of 17-allylamino-17- demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clinical prostate cancer 2005;4(2):138-41.
252. Herawi M, Parwani AV, Irie J, Epstein JI. Small glandular proliferations on needle biopsies: most common benign mimickers of prostatic adenocarcinoma sent in for expert second opinion. The American journal of surgical pathology 2005;29(7):874-80.
253. Hernandez DJ, Epstein JI, Trock BJ, Tsuzuki T, Carter HB, Walsh PC. Radical retropubic prostatectomy. How often do experienced surgeons have positive surgical margins when there is extraprostatic extension in the region of the neurovascular bundle? The Journal of urology 2005;173(2):446-9.
254. Hosler GA, Epstein JI. Basal cell hyperplasia: an unusual diagnostic dilemma on prostate needle biopsies. Human pathology 2005;36(5):480-5.
255. Isaacs JT. New strategies for the medical treatment of prostate cancer. BJU international 2005;96 Suppl 2:35-40.
256. Lin KS, Luu A, Baidoo KE, et al. A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation. Bioconjugate chemistry 2005;16(1):43-50.
257. Lindstrom S, Wiklund F, Jonsson BA, et al. Comprehensive genetic evaluation of common E-cadherin sequence variants and prostate cancer risk: strong confirmation of functional promoter SNP. Human genetics 2005;118(3-4):339-47.
258. Lokeshwar VB, Habuchi T, Grossman HB, et al. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology 2005;66(6 Suppl 1):35-63.
259. Martinez AA, Demanes DJ, Galalae R, et al. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime. International journal of radiation oncology, biology, physics 2005;62(5):1322-31.
260. Minnery CH, Getzenberg RH. Benign prostatic hyperplasia cell line viability and modulation of jm-27 by doxazosin and Ibuprofen. The Journal of urology 2005;174(1):375-9.
261. Myers-Irvin JM, Landsittel D, Getzenberg RH. Use of the novel marker BLCA-1 for the detection of bladder cancer. The Journal of urology 2005;174(1):64-8.
262. Myers-Irvin JM, Van Le TS, Getzenberg RH. Mechanistic analysis of the role of BLCA-4 in bladder cancer pathobiology. Cancer research 2005;65(16):7145-50.
263. Narla G, Difeo A, Reeves HL, et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer research 2005;65(4):1213-22.
264. Ouyang X, DeWeese TL, Nelson WG, Abate-Shen C. Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis. Cancer research 2005;65(15):6773-9.
265. Parsons JK, Carter HB, Platz EA, Wright EJ, Landis P, Metter EJ. Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiol Biomarkers Prev 2005;14(9):2257-60.
266. Paul B, Dhir R, Landsittel D, Hitchens MR, Getzenberg RH. Detection of prostate cancer with a blood-based assay for early prostate cancer antigen. Cancer research 2005;65(10):4097-100.
267. Platz EA, Leitzmann MF, Rifai N, et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiol Biomarkers Prev 2005;14(5):1262-9.
268. Platz EA, Pollak MN, Leitzmann MF, Stampfer MJ, Willett WC, Giovannucci E. Plasma insulin-like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA era. Cancer Causes Control 2005;16(3):255-62.
269. Platz EA, Rohrmann S, Pearson JD, et al. Nonsteroidal anti-inflammatory drugs and risk of prostate cancer in the Baltimore Longitudinal Study of Aging. Cancer Epidemiol Biomarkers Prev 2005;14(2):390-6.
270. Qian DZ, Ren M, Wei Y, et al. In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells. The Prostate 2005;64(1):20-8.
271. Rodriguez R, Pozuelo JM, Martin R, Arriazu R, Santamaria L. Stereological quantification of nerve fibers immunoreactive to PGP 9.5, NPY, and VIP in rat prostate during postnatal development. Journal of andrology 2005;26(2):197-204.
272. Rogers CG, Parwani A, Tekes A, Schoenberg MP, Epstein JI. Carcinosarcoma of the prostate with urothelial and squamous components. The Journal of urology 2005;173(2):439-40.
273. Rohrmann S, Crespo CJ, Weber JR, Smit E, Giovannucci E, Platz EA. Association of cigarette smoking, alcohol consumption and physical activity with lower urinary tract symptoms in older American men: findings from the third National Health And Nutrition Examination Survey. BJU international 2005;96(1):77-82.
274. Rohrmann S, De Marzo AM, Smit E, Giovannucci E, Platz EA. Serum C-reactive protein concentration and lower urinary tract symptoms in older men in the Third National Health and Nutrition Examination Survey (NHANES III). The Prostate 2005;62(1):27-33.
275. Rohrmann S, Paltoo DN, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ. Association of vasectomy and prostate cancer among men in a Maryland cohort. Cancer Causes Control 2005;16(10):1189-94.
276. Rosenbaum E, Hoque MO, Cohen Y, et al. Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy. Clin Cancer Res 2005;11(23):8321-5.
277. Rosenbaum E, Zahurak M, Sinibaldi V, et al. Marimastat in the treatment of patients with biochemically relapsed prostate cancer: a prospective randomized, double-blind, phase I/II trial. Clin Cancer Res 2005;11(12):4437-43.
278. Ross KS, Guess HA, Carter HB. Estimation of treatment benefits when PSA screening for prostate cancer is discontinued at different ages. Urology 2005;66(5):1038-42.
279. Schwarze SR, Luo J, Isaacs WB, Jarrard DF. Modulation of CXCL14 (BRAK) expression in prostate cancer. The Prostate 2005;64(1):67-74.
280. Semmes OJ, Feng Z, Adam BL, et al. Evaluation of serum protein profiling by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry for the detection of prostate cancer: I. Assessment of platform reproducibility. Clinical chemistry 2005;51(1):102-12.
281. Sun J, Wiklund F, Zheng SL, et al. Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. Journal of the National Cancer Institute 2005;97(7):525-32.
282. Sutcliffe S, Giovannucci E, De Marzo AM, Willett WC, Platz EA. Sexually transmitted infections, prostatitis, ejaculation frequency, and the odds of lower urinary tract symptoms. American journal of epidemiology 2005;162(9):898-906.
283. Truskinovsky AM, Partin AW, Kroll MH. Kinetics of tumor growth of prostate carcinoma estimated using prostate-specific antigen. Urology 2005;66(3):577-81.
284. Tsuzuki T, Hernandez DJ, Aydin H, Trock B, Walsh PC, Epstein JI. Prediction of extraprostatic extension in the neurovascular bundle based on prostate needle biopsy pathology, serum prostate specific antigen and digital rectal examination. The Journal of urology 2005;173(2):450-3.
285. Wu CL, Rowlingson AJ, Partin AW, et al. Correlation of postoperative pain to quality of recovery in the immediate postoperative period. Regional anesthesia and pain medicine 2005;30(6):516-22.
286. Xu J, Dimitrov L, Chang BL, et al. A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. American journal of human genetics 2005;77(2):219-29.
287. Xu J, Lowey J, Wiklund F, et al. The interaction of four genes in the inflammation pathway significantly predicts prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2005;14(11 Pt 1):2563-8.
288. Zha S, Ferdinandusse S, Hicks JL, et al. Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer. The Prostate 2005;63(4):316-23.
289. Zha S, Isaacs WB. A nonclassic CCAAT enhancer element binding protein binding site contributes to alpha-methylacyl-CoA racemase expression in prostate cancer. Mol Cancer Res 2005;3(2):110-8.

2006

290. Aggarwal S, Harden JL, Denmeade SR. Synthesis and screening of a random dimeric peptide library using the one-bead-one-dimer combinatorial approach. Bioconjugate chemistry 2006;17(2):335-40.
291. Aggarwal S, Ricklis RM, Williams SA, Denmeade SR. Comparative study of PSMA expression in the prostate of mouse, dog, monkey, and human. The Prostate 2006;66(9):903-10.
292. Aggarwal S, Singh P, Topaloglu O, Isaacs JT, Denmeade SR. A dimeric peptide that binds selectively to prostate-specific membrane antigen and inhibits its enzymatic activity. Cancer research 2006;66(18):9171-7.
293. Baillargeon J, Platz EA, Rose DP, et al. Obesity, adipokines, and prostate cancer in a prospective population-based study. Cancer Epidemiol Biomarkers Prev 2006;15(7):1331-5.
294. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006;106(3):581-8.
295. Bastian PJ, Gonzalgo ML, Aronson WJ, et al. Clinical and pathologic outcome after radical prostatectomy for prostate cancer patients with a preoperative Gleason sum of 8 to 10. Cancer 2006;107(6):1265-72.
296. Bethel CR, Faith D, Li X, et al. Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion. Cancer research 2006;66(22):10683-90.
297. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006;24(24):3979-83.
298. Braga-Basaria M, Muller DC, Carducci MA, Dobs AS, Basaria S. Lipoprotein profile in men with prostate cancer undergoing androgen deprivation therapy. International journal of impotence research 2006;18(5):494-8.
299. Carter HB. Assessing risk: does this patient have prostate cancer? Journal of the National Cancer Institute 2006;98(8):506-7.
300. Carter HB, Ferrucci L, Kettermann A, et al. Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. Journal of the National Cancer Institute 2006;98(21):1521-7.
301. Chang BL, Lange EM, Dimitrov L, et al. Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect. Human genetics 2006;118(6):716-24.
302. Chen CL, Sung J, Cohen M, et al. Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. The Journal of pharmacology and experimental therapeutics 2006;319(2):533-42.
303. Coffey DS, Getzenberg RH, DeWeese TL. Hyperthermic biology and cancer therapies: a hypothesis for the "Lance Armstrong effect". Jama 2006;296(4):445-8.
304. De Marzo AM, Platz EA, Epstein JI, et al. A working group classification of focal prostate atrophy lesions. The American journal of surgical pathology 2006;30(10):1281-91.
305. Dunn TA, Chen S, Faith DA, et al. A novel role of myosin VI in human prostate cancer. The American journal of pathology 2006;169(5):1843-54.
306. Egevad L, Allsbrook WC, Jr., Epstein JI. Current practice of diagnosis and reporting of prostate cancer on needle biopsy among genitourinary pathologists. Human pathology 2006;37(3):292-7.
307. Egevad L, Allsbrook WC, Epstein JI. Current practice of diagnosis and reporting of prostatic intraepithelial neoplasia and glandular atypia among genitourinary pathologists. Mod Pathol 2006;19(2):180-5.
308. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. The Journal of urology 2006;175(3 Pt 1):820-34.
309. Fine SW, Chan TY, Epstein JI. Inverted papillomas of the prostatic urethra. The American journal of surgical pathology 2006;30(8):975-9.
310. Freedland SJ, Giovannucci E, Platz EA. Are findings from studies of obesity and prostate cancer really in conflict? Cancer Causes Control 2006;17(1):5-9.
311. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Partin AW. Time to prostate specific antigen recurrence after radical prostatectomy and risk of prostate cancer specific mortality. The Journal of urology 2006;176(4 Pt 1):1404-8.
312. Freedland SJ, Partin AW. Prostate-specific antigen: update 2006. Urology 2006;67(3):458-60.
313. Freedland SJ, Platz EA, Presti JC, Jr., et al. Obesity, serum prostate specific antigen and prostate size: implications for prostate cancer detection. The Journal of urology 2006;175(2):500-4; discussion 4.
314. Glunde K, Ackerstaff E, Mori N, Jacobs MA, Bhujwalla ZM. Choline phospholipid metabolism in cancer: consequences for molecular pharmaceutical interventions. Molecular pharmaceutics 2006;3(5):496-506.
315. Gong Z, Neuhouser ML, Goodman PJ, et al. Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev 2006;15(10):1977-83.
316. Gonzalgo ML, Bastian PJ, Mangold LA, et al. Relationship between primary Gleason pattern on needle biopsy and clinicopathologic outcomes among men with Gleason score 7 adenocarcinoma of the prostate. Urology 2006;67(1):115-9.
317. Gu Y, Li H, Miki J, et al. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines. Experimental cell research 2006;312(6):831-43.
318. Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: Histologic features and clinical significance. Mod Pathol 2006;19(12):1528-35.
319. Hansel DE, Epstein JI. Sarcomatoid carcinoma of the prostate: a study of 42 cases. The American journal of surgical pathology 2006;30(10):1316-21.
320. Helzlsouer KJ, Erlinger TP, Platz EA. C-reactive protein levels and subsequent cancer outcomes: results from a prospective cohort study. Eur J Cancer 2006;42(6):704-7.
321. Herawi M, Epstein JI. Specialized stromal tumors of the prostate: a clinicopathologic study of 50 cases. The American journal of surgical pathology 2006;30(6):694-704.
322. Herawi M, Kahane H, Cavallo C, Epstein JI. Risk of prostate cancer on first re-biopsy within 1 year following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores sampled. The Journal of urology 2006;175(1):121-4.
323. Herawi M, Montgomery EA, Epstein JI. Gastrointestinal stromal tumors (GISTs) on prostate needle biopsy: A clinicopathologic study of 8 cases. The American journal of surgical pathology 2006;30(11):1389-95.
324. Isaacs JT, Pili R, Qian DZ, et al. Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer. The Prostate 2006;66(16):1768-78.
325. Janssen S, Rosen DM, Ricklis RM, et al. Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug. The Prostate 2006;66(4):358-68.
326. Klassen AC, Curriero F, Kulldorff M, Alberg AJ, Platz EA, Neloms ST. Missing stage and grade in Maryland prostate cancer surveillance data, 1992-1997. American journal of preventive medicine 2006;30(2 Suppl):S77-87.
327. Klassen AC, Platz EA. What can geography tell us about prostate cancer? American journal of preventive medicine 2006;30(2 Suppl):S7-15.
328. Lindstrom S, Zheng SL, Wiklund F, et al. Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. The Prostate 2006;66(16):1729-43.
329. Litvinov IV, Antony L, Dalrymple SL, Becker R, Cheng L, Isaacs JT. PC3, but not DU145, human prostate cancer cells retain the coregulators required for tumor suppressor ability of androgen receptor. The Prostate 2006;66(12):1329-38.
330. Litvinov IV, Vander Griend DJ, Antony L, et al. Androgen receptor as a licensing factor for DNA replication in androgen-sensitive prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America 2006;103(41):15085-90.
331. Litvinov IV, Vander Griend DJ, Xu Y, Antony L, Dalrymple SL, Isaacs JT. Low-calcium serum-free defined medium selects for growth of normal prostatic epithelial stem cells. Cancer research 2006;66(17):8598-607.
332. Liu W, Chang B, Sauvageot J, et al. Comprehensive assessment of DNA copy number alterations in human prostate cancers using Affymetrix 100K SNP mapping array. Genes, chromosomes & cancer 2006;45(11):1018-32.
333. Makarov DV, Carter HB. The discovery of prostate specific antigen as a biomarker for the early detection of adenocarcinoma of the prostate. The Journal of urology 2006;176(6 Pt 1):2383-5.
334. Makarov DV, Humphreys EB, Mangold LA, et al. Pathological outcomes and biochemical progression in men with T1c prostate cancer undergoing radical prostatectomy with prostate specific antigen 2.6 to 4.0 vs 4.1 to 6.0 ng/ml. The Journal of urology 2006;176(2):554-8.
335. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. Jama 2006;296(19):2351-61.
336. Markushin Y, Gaikwad N, Zhang H, et al. Potential biomarker for early risk assessment of prostate cancer. The Prostate 2006;66(14):1565-71.
337. Mavropoulos JC, Isaacs WB, Pizzo SV, Freedland SJ. Is there a role for a low-carbohydrate ketogenic diet in the management of prostate cancer? Urology 2006;68(1):15-8.
338. Michaud DS, Daugherty SE, Berndt SI, et al. Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer research 2006;66(8):4525-30.
339. Montgomery EA, Shuster DD, Burkart AL, et al. Inflammatory myofibroblastic tumors of the urinary tract: a clinicopathologic study of 46 cases, including a malignant example inflammatory fibrosarcoma and a subset associated with high-grade urothelial carcinoma. The American journal of surgical pathology 2006;30(12):1502-12.
340. Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. The American journal of surgical pathology 2006;30(9):1184-8.
341. Palapattu GS, Meeker A, Harris T, et al. Epithelial architectural destruction is necessary for bone marrow derived cell contribution to regenerating prostate epithelium. The Journal of urology 2006;176(2):813-8.
342. Parsons JK, Carter HB, Partin AW, et al. Metabolic factors associated with benign prostatic hyperplasia. The Journal of clinical endocrinology and metabolism 2006;91(7):2562-8.
343. Parwani AV, Herawi M, Epstein JI. Pleomorphic giant cell adenocarcinoma of the prostate: report of 6 cases. The American journal of surgical pathology 2006;30(10):1254-9.
344. Parwani AV, Marlow C, Demarzo AM, et al. Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer. The American journal of surgical pathology 2006;30(10):1231-6.
345. Platz EA, Leitzmann MF, Visvanathan K, et al. Statin drugs and risk of advanced prostate cancer. Journal of the National Cancer Institute 2006;98(24):1819-25.
346. Qian DZ, Kato Y, Shabbeer S, et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006;12(2):634-42.
347. Raman V, Artemov D, Pathak AP, et al. Characterizing vascular parameters in hypoxic regions: a combined magnetic resonance and optical imaging study of a human prostate cancer model. Cancer research 2006;66(20):9929-36.
348. Richman JM, Carter HB, Hanna MN, et al. Efficacy of periprostatic local anesthetic for prostate biopsy analgesia: a meta-analysis. Urology 2006;67(6):1224-8.
349. Rogers CG, Gonzalgo ML, Yan G, et al. High concordance of gene methylation in post-digital rectal examination and post-biopsy urine samples for prostate cancer detection. The Journal of urology 2006;176(5):2280-4.
350. Rohrmann S, Fallin MD, Page WF, et al. Concordance rates and modifiable risk factors for lower urinary tract symptoms in twins. Epidemiology (Cambridge, Mass 2006;17(4):419-27.
351. Rohrmann S, Fallin MD, Page WF, et al. Re: "Obesity and hormone-dependent tumors: cohort and co-twin control studies based on the Swedish twin registry". International journal of cancer 2006;118(3):785.
352. Schowinsky JT, Epstein JI. Distorted rectal tissue on prostate needle biopsy: a mimicker of prostate cancer. The American journal of surgical pathology 2006;30(7):866-70.
353. Simons JW, Carducci MA, Mikhak B, et al. Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naive prostate cancer. Clin Cancer Res 2006;12(11 Pt 1):3394-401.
354. Singh P, Uzgare A, Litvinov I, Denmeade SR, Isaacs JT. Combinatorial androgen receptor targeted therapy for prostate cancer. Endocrine-related cancer 2006;13(3):653-66.
355. Sinibaldi VJ, Elza-Brown K, Schmidt J, et al. Phase II evaluation of docetaxel plus exisulind in patients with androgen independent prostate carcinoma. American journal of clinical oncology 2006;29(4):395-8.
356. Small EJ, Carducci MA, Burke JM, et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther 2006;14(1):107-17.
357. Sohoel H, Jensen AM, Moller JV, et al. Natural products as starting materials for development of second-generation SERCA inhibitors targeted towards prostate cancer cells. Bioorganic & medicinal chemistry 2006;14(8):2810-5.
358. Strock CJ, Park JI, Nakakura EK, et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer research 2006;66(15):7509-15.
359. Sun J, Hsu FC, Turner AR, et al. Meta-analysis of association of rare mutations and common sequence variants in the MSR1 gene and prostate cancer risk. The Prostate 2006;66(7):728-37.
360. Sun J, Wiklund F, Hsu FC, et al. Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2006;15(3):480-5.
361. Sutcliffe S, Giovannucci E, Alderete JF, et al. Plasma antibodies against Trichomonas vaginalis and subsequent risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006;15(5):939-45.
362. Sutcliffe S, Giovannucci E, De Marzo AM, Leitzmann MF, Willett WC, Platz EA. Gonorrhea, syphilis, clinical prostatitis, and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006;15(11):2160-6.
363. Sutcliffe S, Zenilman JM, Ghanem KG, et al. Sexually transmitted infections and prostatic inflammation/cell damage as measured by serum prostate specific antigen concentration. The Journal of urology 2006;175(5):1937-42.
364. Tamas EF, Epstein JI. Prognostic significance of paneth cell-like neuroendocrine differentiation in adenocarcinoma of the prostate. The American journal of surgical pathology 2006;30(8):980-5.
365. Tan PH, Tan HW, Tan Y, Lim CN, Cheng C, Epstein JI. Is high-grade prostatic intraepithelial neoplasia on needle biopsy different in an Asian population: a clinicopathologic study performed in Singapore. Urology 2006;68(4):800-3.
366. Tande AJ, Platz EA, Folsom AR. The metabolic syndrome is associated with reduced risk of prostate cancer. American journal of epidemiology 2006;164(11):1094-102.
367. Veltri RW, Khan MA, Marlow C, et al. Alterations in nuclear structure and expression of proPSA predict differences between native Japanese and Japanese-American prostate cancer. Urology 2006;68(4):898-904.
368. Wang X, Wang F, Taniguchi K, et al. Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk. Cancer research 2006;66(21):10302-7.
369. Warlick C, Trock BJ, Landis P, Epstein JI, Carter HB. Delayed versus immediate surgical intervention and prostate cancer outcome. Journal of the National Cancer Institute 2006;98(5):355-7.
370. Warlick CA, Allaf ME, Carter HB. Expectant treatment with curative intent in the prostate-specific antigen era: triggers for definitive therapy. Urologic oncology 2006;24(1):51-7.
371. Xia Q, Sung J, Chowdhury W, et al. Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo. Cancer research 2006;66(14):7237-44.
372. Xu J, Sauvageot J, Ewing CM, et al. Germline ATBF1 mutations and prostate cancer risk. The Prostate 2006;66(10):1082-5.
373. Xu Y, Dalrymple SL, Becker RE, Denmeade SR, Isaacs JT. Pharmacologic basis for the enhanced efficacy of dutasteride against prostatic cancers. Clin Cancer Res 2006;12(13):4072-9.
374. Yegnasubramanian S, Lin X, Haffner MC, DeMarzo AM, Nelson WG. Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. Nucleic acids research 2006;34(3):e19.
375. Zheng SL, Ju JH, Chang BL, et al. Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function. Cancer research 2006;66(1):69-77.
376. Zheng SL, Liu W, Wiklund F, et al. A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study. The Prostate 2006;66(14):1556-64.

B. Scientific and Administrative Leadership

(1) Johns Hopkins Prostate Cancer SPORE Program Leadership (Principal Investigator and Co-Principal Investigator)

During the initial funded period, the Johns Hopkins Prostate Cancer SPORE Program was assembled and directed by Donald S. Coffey, Ph.D., a recognized national leader in prostate cancer research.  Beginning July 1, 2001, Dr. Coffey relinquished his position as SPORE Program Principal Investigator, and was replaced by William G. Nelson, M.D., Ph.D., who navigated the SPORE Program through its last competitive renewal application and will continue as the Principal Investigator through the next funding period, along with Robert H. Getzenberg, Ph.D., now Co-Principal Investigator. 

Dr. Nelson, originally a recipient of SPORE Career Development support, has become an international leader in the area of prostate cancer translational research.  He completed his M.D. and Ph.D. training at the Johns Hopkins University School of Medicine, earning honors for both research and clinical excellence, and then pursued Internal Medicine residency training and Medical Oncology fellowship training at the Johns Hopkins Hospital, earning American Board of Internal Medicine certification in both disciplines.  Now a Professor of Oncology, Urology, Pharmacology, Medicine, Radiation Oncology, and Pathology at the Johns Hopkins University School of Medicine, with a Joint Appointment in Environmental Health Sciences at the Johns Hopkins University Bloomberg School of Public Health, Dr. Nelson directs a research laboratory focused on discovering new strategies for prostate cancer treatment and prevention, and manages a clinical practice focused on developing these new treatment and prevention approaches in early “proof-of-principle” prostate clinical trials.  A member of the Johns Hopkins Prostate Cancer SPORE Program since its inception, he has also secured peer-reviewed funding from the NCI and from the Prostate Cancer Foundation, an organization dedicated to prostate cancer research, for his prostate cancer studies.  Within the SKCCC, Dr. Nelson serves as the Director of the Prostate Cancer Program, one of eleven NCI-supported formal Cancer Center Programs, and as the Associate Cancer Center Director for Translational Research.  Dr. Nelson also serves as the Principal Investigator for the NCI-funded Molecular Targets Training Program, dedicated to providing clinical oncology fellows specific training in translational research, and for the Howard University Cancer Center-SKCCC Partnership Program, dedicated to building cancer research capabilities at Howard and enhancing minority subject recruitment to cancer research programs at Johns Hopkins. 

Outside of Johns Hopkins, Dr. Nelson has also become a recognized leader in prostate cancer and in translational cancer research, invited to author key reviews on prostate cancer in major journals (Isaacs W et al. Cancer Cell 2002; 2:113-6; DeMarzo AM et al. Lancet 2003; 361: 955-64; Nelson WG et al. New Engl J Med 2003; 349: 366-81).  He was a Co-Editor of the Report to the Nation on Prostate Cancer, 2004 for the Prostate Cancer Foundation and Medscape, Inc., and the lead author of the chapter on “Prostate Cancer” in Clinical Oncology, 3rd Edition, Abeloff, M.D., Armitage, J.O., Niederhuber, J.E., Kastan, M.B., and McKenna, W.G. (Eds.), for 2004, and again for 2007.  A member of the American Association for Cancer Research, he has served as a member of the Board of Directors, the Clinical Research Committee (he was a former Chairman of this Committee), the Public Education Committee, the Special Conferences Committee, and the Science Policy and Legislative Affairs Committee (he currently Chairs this Committee).  Dr. Nelson also serves as the President of National Coalition for Cancer Research, on the Scientific Advisory Board of the Prostate Cancer Foundation, and on the Scientific Advisory Boards of several companies focused on the development of new technologies and treatments for human cancer.  He is a Senior Editor of Cancer Research and an Associate Editor of Clinical Cancer Research, and frequently reviews grant proposals for the National Institutes of Health, the Department of Veterans Affairs, CaP CURE, the New York Academy of Medicine, and the Department of Defense.  Finally, Dr. Nelson has been one of three Co-Chairs of the NCI Translational Research Working Group (TRWG), a diverse team of sixty key translational research stakeholders charged by the Cancer Institute Director with reengineering the federally-funded translational research enterprise, including the SPORE Programs.  The final TRWG Report will be presented to the National Cancer Advisory Board in June of 2007.  With his resolute focus on prostate cancer translational research, his familiarity with the Johns Hopkins Prostate Cancer SPORE research activities, his appointments in most of the critical Departments in the Johns Hopkins University School of Medicine for SPORE Research Projects and Core Resources, and his leadership positions both in the SKCCC and nationally, Dr. Nelson is well-suited to act as Principal Investigator of the Johns Hopkins Prostate Cancer SPORE Program, and authorized to develop the Prostate Cancer SPORE Program scientific agenda.   

Dr. Getzenberg has been contributing to the prostate cancer field for 19 years.  He obtained his Ph.D. working in the laboratory of Dr. Donald S. Coffey at the Brady Urological Institute.  He then went on to complete a postdoctoral fellowship at Yale University, and for 11 years served on the faculty of the University of Pittsburgh rising to the rank of Professor of Urology, Pathology, and Pharmacology, and serving as the Director of Urology Research.  On January 1, 2005, he assumed the leadership of the Brady Urological Research Institute taking over from his mentor Dr. Donald S. Coffey.  Dr. Getzenberg currently serves as not only the Director of Urology Research, but also as Professor of Urology, Oncology, and Pharmacology at The Johns Hopkins University School of Medicine.  Throughout his career, Dr. Getzenberg has published a number of seminal manuscripts in the fields of prostate cancer and cell and molecular biology.  In addition, he has had consistent peer-reviewed research support to fund his efforts to discover and validate new prostate cancer biomarkers.  Well recognized nationally and internationally for his research accomplishments, Dr. Getzenberg currently serves as President of the Society for Basic Urologic Research (SBUR).  In this position, he has had the opportunity to influence urologic research throughout the world by organizing meetings and special conferences, including the Prouts Neck Prostate Cancer Conference series, activities which has allowed him to collaborate with Dr. Nelson even before joining the Johns Hopkins faculty.  Dr. Getzenberg is also a current participant in a U01 application to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) proffered by a consortium through the NIDDK examining BPH biomarkers.  For this multi-institutional consortium, Dr. Getzenberg was selected as the Chairman of the Steering Committee, responsible for organizing and coordinating the seven individual sites intending to cooperate within this consortium.  As the Director of Urology Research at the Brady Urological Institute and Department of Urology at Johns Hopkins, Dr. Getzenberg coordinates all research activities, supervises research administrative staff, and manages the Institute’s biospecimen collections.  He likewise oversees the allocation of the $1,000,000 that is distributed annually as part of the Patrick C. Walsh Prostate Cancer Research Fund, a major institutional commitment to the Prostate Cancer SPORE Program.  With his experience and achievements in the basic molecular biology of human prostate cancer, his knowledge of the Johns Hopkins Prostate Cancer SPORE research activities, his proven ability to direct large multi-disciplinary research projects involving many investigators, and his productive relationship with Dr. Nelson, Dr. Getzenberg is well-suited to act as the Co-Principal Investigator of the Johns Hopkins Prostate Cancer SPORE Program and authorized to collaborate with Dr. Nelson in developing the Prostate Cancer SPORE Program scientific agenda.

As Principal Investigator, Dr. Nelson will be primarily responsible for scientific leadership for the SPORE Program, including facilitating collaborations between different SPORE investigators in different academic Departments, coordinating interactions between various SPORE Research Projects and Cores, monitoring the effectiveness and productivity of SPORE activities, representing the interests of the SPORE Program at the SKCCC and at the Johns Hopkins University School of Medicine, and promoting interactions between the John Hopkins Prostate Cancer SPORE and Prostate Cancer SPORE Programs at other institutions.  Dr. Nelson is authorized to be ultimately responsible for any significant changes in funding allocations for Research Projects, Core Resources, Developmental Research Projects, and Career Development Projects.  As Principal Investigator, Dr. Nelson will submit yearly progress reports to the NCI, ensure compliance with NCI SPORE Program requirements and with Johns Hopkins University School of Medicine policies and guidelines for biomedical research, participate in monthly Prostate Cancer SPORE Principal Investigator conference calls, and attend annual SPORE Program Principal Investigator meetings, working with other SPORE Principal Investigators to identify shared impediments to translational research progress across all SPORE Programs (eg. helping the NCI implement changes recommended by the Translational Research Working Group), and to develop strategies to rapidly exploit new translational research opportunities, using SPORE Program assets, as these new opportunities arise.  As Co-Principal Investigator, Dr. Getzenberg will assist Dr. Nelson in all aspects of his scientific leadership.

Summary of responsibilities of Principal Investigator (P.I.) and Co-Principal Investigator (Co-P.I.):

• Scientific leadership for the SPORE Program;
• Chair Executive Committee meetings each month;
• Facilitate collaborations between SPORE Research Projects, between Johns Hopkins Prostate Cancer SPORE investigators and other investigators at Johns Hopkins, and between the Johns Hopkins Prostate Cancer SPORE Program and other SPORE programs, to maximize impact of SPORE Program translational research agenda;
• Monitor SPORE Program progress and effectiveness;
• Propose changes in SPORE Program funding allocation or research direction to Internal Oversight Committee for approval;
• Present new Career Development and Developmental Research Projects to Internal Oversight Committee for approval;
• Prepare a Yearly Progress Report, with recommendations from External Scientific Advisory Board and minutes of monthly Executive Committee meetings, for review by Internal Oversight Committee;
• Represent interests of the SPORE Program to the SKCCC and Johns Hopkins University School of Medicine;
• Submit a Progress Report each year to the NCI;
• Organize responses to new initiatives and requests by the NCI;
• Participate in monthly Prostate Cancer SPORE Principal Investigator conference calls;
• Attend yearly SPORE Program Directors meeting;
• Ensure compliance of SPORE Program with all research requirements and policies of the NCI and the Johns Hopkins University School of Medicine.

(2) Johns Hopkins Prostate Cancer SPORE Internal Oversight Committee

To assist Drs. Nelson and Isaacs in the strategic management of SPORE Program activities, an Internal Oversight Committee, comprised of key institutional leaders at the Johns Hopkins University School of Medicine and Bloomberg School of Health, has been formed (Table 3).  The Internal Oversight Committee Members include the Chairmen of the Departments of Oncology, Urology, and Radiation Oncology, and the Vice Dean for Research, at the Johns Hopkins University School of Medicine, as well as the Chairman of the Department of Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health.  This Committee, which will meet on a yearly basis (and more often if needed) with Drs. Nelson and Getzenberg, will review SPORE Program progress, participate in strategic planning for SPORE research activities, help coordinate the allocation of institutional resources (laboratory space, faculty recruitment, etc.) to best exploit new translational research opportunities arising during the conduct of SPORE Program research, and ensure coordination between the SPORE Program and other Programs at the SKCCC and Johns Hopkins University School of Medicine.  Drs. Nelson and Getzenberg will submit a SPORE Program progress report to the Committee each year (separate from the yearly report forwarded to the NCI) documenting the productivity of each of the Research Projects and the utility of each of the Core Resources.  This yearly progress report will also contain recommendations provided by the Johns Hopkins Prostate Cancer SPORE External Scientific Advisory Board (which will also meet yearly to review progress of specific Research Projects; see below).  The Johns Hopkins Prostate Cancer SPORE Program aims to remain flexible enough in its funding priorities to discontinue unproductive Research Projects and initiate new Research Projects from promising Developmental Research activities.  After review of the yearly progress report at its annual meeting, the Internal Oversight Committee will consider proposals for any changes in research priorities or funding allocations proffered by Drs. Nelson and Getzenberg, and approve such changes by vote.  In addition, each year, Drs. Nelson and Getzenberg will present the results of peer-review for applications for Developmental Research and Career Development support to the Internal Oversight Committee for final review and approval.

Table 3.  Johns Hopkins Prostate Cancer SPORE Internal Oversight Committee.

Summary of Johns Hopkins Prostate Cancer SPORE Program Internal Oversight Committee responsibilities:

• Meet on a yearly basis;
• Evaluate SPORE Program Progress, including productivity of Research Projects and effectiveness of Core Resources;
• Review Yearly Progress Report submitted to the NCI;
• Review Yearly Progress Report prepared by Drs. Nelson and Isaacs after the External Scientific Advisory Board meeting;
• Consider proposals from Drs. Nelson and Getzenberg to discontinue Research Projects or to initiate new Research Projects and approve by vote;
• Consider nominees presented by Drs. Nelson and Getzenberg for Career Development support and for Developmental Research support and approve by vote;
• Participate in strategic planning for future Prostate Cancer SPORE Program activities.

(3) Johns Hopkins Prostate Cancer SPORE External Scientific Advisory Board

            To assist Drs. Nelson and Getzenberg in the evaluation of SPORE Program activities, and to assist individual SPORE Research Project Co-Principal Investigators in the pursuit of their study aims, an External Scientific Advisory Board, comprised of key leaders from the cancer research community (Table 4), has been formed.  This Advisory Board, which will meet on a yearly basis at Johns Hopkins at the Prostate Cancer Research Day (and more often by conference call if needed) with Drs. Nelson and Getzenberg, will review the progress of each of the SPORE Research Projects and Developmental Research Projects, participate in the evaluation of individual SPORE Research Project productivity, and make recommendations concerning prioritization of new research opportunities as new discoveries are made.  At each yearly External Scientific Advisory Board meeting at the Prostate Cancer Research Day, the Research Project Co-Principal Investigators, Developmental Research Principal Investigators, Career Development, and Patrick C. Walsh Prostate Cancer Research Fund Investigators will present their interval research findings.  Subsequently, the Advisory Board will meet with Drs. Nelson and Getzenberg to discuss SPORE Program progress and productivity.  Drs. Nelson and Getzenberg will include the impressions and recommendations of the External Scientific Advisory Board in their yearly SPORE Program progress report to the Internal Oversight Committee.

Table 4.  Johns Hopkins Prostate Cancer External Scientific Advisory Board.

Summary of Johns Hopkins Prostate Cancer SPORE Program External Scientific Advisory Board responsibilities:

• Meet on a yearly basis at the Prostate Cancer Research Day to hear presentations from each of the Prostate Cancer SPORE Program investigators;
• Meet privately with Drs. Nelson and Getzenberg after hearing SPORE investigator presentations;
• Evaluate the progress and productivity of individual SPORE Research Projects, Developmental Research Projects, Career Development Projects, and Core Resources;
• Make recommendations for any changes in the prioritization of the SPORE Research Project portfolio;
• Assist Drs. Nelson and Getzenberg in preparing a Yearly Progress report for consideration by the Internal Oversight Committee.

(4) Johns Hopkins Prostate Cancer SPORE Executive Committee

To manage the day-to-day workings of the Johns Hopkins Prostate Cancer SPORE Program, Drs. Nelson and Getzenberg will be supported by an Executive Committee, comprised of senior scientific leaders, from different major academic Departments at the Johns Hopkins University School of Medicine, who also serve as Co-Principal Investigators of Research Projects or Core Resources in the SPORE portfolio (see Table 5).  This Executive Committee will meet monthly to review and evaluate SPORE Program Progress, to respond to new initiatives from the NCI (eg. new supplemental SPORE funding opportunities, RAID, RAPID, etc.), to help facilitate collaborative interactions between the Johns Hopkins Prostate Cancer SPORE and Prostate Cancer SPOREs at other institutions, and to ensure coordination between Prostate Cancer SPORE Research Projects and Core Resources.  The Executive Committee will meet on a monthly basis.  Two SPORE Research Projects should be reviewed at each Executive Committee meeting; in this way, each SPORE Research Project should be fully reviewed at least 2-3 times per year.  The Executive Committee will have the responsibility of securing scientific reviews of all applications for Prostate Cancer SPORE Program Developmental Research Projects and Career Development Projects, a process fully integrated with the reviews of applications to the Patrick C. Walsh Prostate Cancer Research Fund.  The SPORE Developmental Research and Career Development Projects will be assigned priority scores, which will be used by Drs. Nelson and Getzenberg as they identify Projects suitable for funding, and will also be made available to the Internal Oversight Committee as they provide final approval for the Projects recommended for SPORE Program funding.

Table 5.  Johns Hopkins Prostate Cancer SPORE Executive Committee.

Summary of Johns Hopkins Prostate Cancer SPORE Program Executive Committee responsibilities:

• Meet on a monthly basis;
• Evaluate SPORE Program Progress, including productivity of Research Projects and effectiveness of Core Resources;
• Respond to new initiatives from the NCI;
• Facilitate collaborative research ventures between the Johns Hopkins Prostate Cancer SPORE Program and SPORE Programs at other institutions;
• Orchestrate peer-review of new applications for Career Development, Developmental Research, and Patrick C. Walsh Prostate Cancer Research Fund Projects.

(5) Scientific Decision-Making for the Prostate Cancer SPORE Program

The day-to-day decision-making for individual SPORE Research Projects, for Core Resources, for Developmental Research Projects, and for Career Development Projects, will be accomplished by Project Principal Investigators and Core Directors.  If a significant change in any of the SPORE Program components needs to be made at any time for any reason, all relevant issues will first be presented and discussed at a monthly Executive Committee meeting.  The Executive Committee will prepare a report outlining possible plans of action and documenting any consensus reached as to the best plan.  The Executive Committee will consider all necessary circumstances, and will seek the input from the External Scientific Advisory Board, as it drafts its report.  The SPORE Program Principal Investigator and Co-Principal Investigator will then select a plan of action, and then present their rationale, along with the Executive Committee report, to the Internal Oversight Committee for final approval.  As an example, if a SPORE Program Research Project has been unproductive, or been scientifically productive, but has not progressed toward a translational research objective, or has considered a major change in research direction, the Executive Committee might recommend discontinuing SPORE Program support, conditionally continuing SPORE Program support until independent NCI R01 funding for the Project research is obtained, or securing outside peer-review, with the help of the Scientific Advisory Board, for new Project research aims.  As a second example, if a Developmental Research Project or Patrick C. Walsh Prostate Cancer Research Fund Project leads to a critical new translational research opportunity, the Executive Committee, after soliciting input from the External Scientific Advisory Board, might recommend the creation of a new SPORE Program Research Project, additional SPORE Program funding until support from another funding source becomes available, or appealing to the Internal Oversight Committee for allocation of institutional resources.  In this way, critical program decisions will be made by the Principal Investigator, with the help of the Co-Principal Investigator, after considering recommendations of the Executive Committee and External Scientific Advisory Board.  All programmatic decisions will be subject to review and approval by the Internal Oversight Committee.

Using this approach, in preparation for submission of this revised competitive renewal Prostate Cancer SPORE Program proposal, the Principal Investigator, Dr. Nelson, and the Co-Principal Investigator, Dr. Getzenberg, managed a six-month-long process of prioritizing six new Research Projects, from a candidate pool of more than twice as many preliminary applications, to establish the current Research Project portfolio.  Previous ongoing reviews of the currently funded collection of Research Projects, with the input of Internal and External Advisors, had indicated that each of these Projects would advance to translational research goals, or to productive failure, by the spring of 2008.  Hence, a new collection of Research Projects will be advanced. 

C. Institutional Commitment

(1) The Priority of SPORE Programs at Johns Hopkins

The Johns Hopkins University is highly committed to the Prostate Cancer SPORE Program and its integration in the Comprehensive Cancer Center, the School of Medicine, and the Bloomberg School of Public Health.  The Cancer Center fully contains two academic Departments at the Johns Hopkins University School of Medicine, and Dr. Martin D. Abeloff, the Cancer Center Director and Chairman of Oncology, and Dr. Theodore L. DeWeese, Chairman of Radiation Oncology, report to the Dean of the School of Medicine and CEO of Johns Hopkins Medicine, Dr. Edward Miller.  Dr. Abeloff is also the Oncologist-in-Chief of the Johns Hopkins Hospital; Dr. DeWeese serves at the Radiation Oncologist-in-Chief.  Dr. Alan W. Partin, Chairman of Urology and Urologist-in-Chief, and Dr. J. Brooks Jackson, Chairman of Pathology and Pathologist-in-Chief, also report directly to Dr. Miller.  Within the Comprehensive Cancer Center, the Prostate Cancer SPORE Program is encompassed within a formal Prostate Cancer Program, directed by Prostate Cancer SPORE Principal Investigator Dr. William G. Nelson, who reports directly to the Cancer Center Director, Dr. Martin D. Abeloff.  Dr. Nelson also serves as the Associate Cancer Center Director for Translational Research, on the Cancer Center Executive Committee, responsible for budget oversight, and on the Cancer Center Research Council, along with Cancer Center Division Directors, Program Leaders, and Principal Investigators of other SPORE Programs, to advise Dr. Abeloff on research directions, faculty recruitment, and allocation of resources at the Cancer Center.  Dr. Robert H. Getzenberg, the Prostate Cancer SPORE Co-Principal Investigator, serves as the Research Director of the Department of Urology and reports directly to the Chairman of Urology, Dr. Alan W. Partin.  As Research Director, Dr. Getzenberg advises Dr. Partin on research directions, faculty recruitment, and allocation of resources in the Department of Urology.  With their leadership positions in the Comprehensive Cancer Center and Department of Urology, Drs. Nelson and Getzenberg are formally authorized to develop the scientific agenda of the Prostate Cancer SPORE Program, prioritizing Research Projects, Developmental Research Projects, and Career Development Projects.  To promote collaboration across academic Departments, Drs. Partin, Getzenberg, and almost all of the other Prostate Cancer SPORE Program investigators, have formal academic appointments in the Comprehensive Cancer Center.

(2) Institutional Plans to Strengthen the Prostate Cancer SPORE Program Capabilities

Johns Hopkins has specifically made a range of substantial commitments to the Prostate Cancer SPORE including:

(i) Space

The School of Medicine has committed 18,000 gross ft2 in the Bunting-Blaustein Cancer Research Building (CRB-1), 1,500 gross ft2 in the new David H. Koch Cancer Research Building (CRB-2), 7,500 gross ft2 in the Brady Urological Institute, and 4,000 gross ft2 in the Department of Pathology to prostate cancer research.  The CRB-1 houses the offices and laboratories of SPORE investigators Drs. William G. Nelson, John T. Isaacs, Charles G. Drake, Samuel R. Denmeade, Theodore L. DeWeese, Michael A. Carducci, Srinivasan Yegnasubramanian, and Angelo M. DeMarzo.  CRB-2, built since the last SPORE Program renewal, houses the laboratory of SPORE investigator Dr. Theodore L. DeWeese.  Dedicated space for Biostatistical Core activities is present in a building adjacent to the CRB-1.  In addition to the new David H. Koch Cancer Research Building (CRB-2), the SKCCC has constructed a new Albert H. Owens Auditorium in a building that connects CRB-1 and CRB-2.

The Brady Urological Institute, located on two floors of the Marburg Building, currently contains the offices and laboratories of SPORE investigators Drs. Robert H. Getzenberg, William B. Isaacs, Alan W. Partin, Shawn E. Lupold, and Bruce W. Trock.  In order to accommodate the growing research activities in prostate cancer, the Institute has been allocated a floor in the Park Building, immediately adjacent to the Marburg Building, which will house a number of Prostate Cancer SPORE investigators as well as other prostate cancer researchers.  The new space commenced its remodeling in May of 2007 and will be ready for occupancy by the end of the 2007 calendar year.  This space comprises approximately 13,000 ft2 of total space, with 13 faculty offices, room for support staff, and 3,800 ft2 of open research laboratories.  The architectural design emphasizes the interactions/communication between the research and clinical faculty and staff: the laboratory has a floor-to-ceiling glass wall and the faculty offices have glass walls as well such that all who visit will be able to see team research underway.  Drs. Patrick C. Walsh, Donald S. Coffey, Shawn E. Lupold, Mark L. Gonzalgo, and others, will be located in this new facility, and there is designated office/laboratory space for the recruitment of two new faculty members.  The support space will be an open configuration, ample enough to house administrative assistants, research coordinators, fellows, database support personnel, etc.    

The Department of Pathology supports offices and laboratories for Drs. Jonathan I. Epstein, Alan K. Meeker, David M. Berman, and Angelo De Marzo.  Clinical space for the conduct of clinical trials is available in the clinical facilities of the Departments of Oncology, Urology, and Pathology but particularly in the Weinberg Comprehensive Cancer Center building.

(ii) Recruitment

Since the last Prostate Cancer SPORE Program renewal, Johns Hopkins has provided start-up funds for the recruitment of several new investigators focused on prostate cancer translational research, including:

1. Dr. Srinivasan Yegnasubramanian, a molecular biologist (Oncology), with an interest in the development and application of genomic technologies for the study of prostate cancer epigenetics;
2. Dr. Mark L. Gonzalgo, a physician-scientist (Urology), with an interest in prostate cancer epigenetics as molecular biomarkers for prostate cancer detection, diagnosis, and staging;      
3. Dr. Robert H. Getzenberg (Director of Research for the Brady Urological Institute and SPORE Program Co-Principal Investigator), a molecular biologist (Urology), with an interest in proteomics technologies applied to the discovery of new cancer biomarkers;
4. Dr. Edward M. Schaeffer, a physician-scientist (Urology), with an interest in developmental signaling pathways and the pathogenesis of prostate cancer;
5. Dr. Shawn E. Lupold, a molecular biologist (Urology), with an interest in aptamer and nanotechnologies in new treatment discovery and development;
6. Dr. Danny Y. Song, a clinician and clinical researcher (Radiation Oncology), with an interest in prostate cancer brachytherapy;
7. Dr. Alan K. Meeker, a cell and molecular biologist (Pathology), with an interest in telomere dysfunction during prostatic carcinogenesis;               
8. Dr. David M. Berman, a physician-scientist (Pathology), with an interest in the development of the genitourinary tract and genitourinary cancers;
9. Dr. George J. Netto, a physician-scientist (Pathology), with an interest in the development of new prostate cancer tissue biomarkers to aid in diagnosis and risk stratification;
10. Dr. Jean G. Ford, a physician and population scientist (Epidemiology), with an interest in health disparities in prostate cancer and other cancers, and in community outreach and research.

(iii) Shared Resources

Through the Comprehensive Cancer Center, SPORE investigators have access to several long-standing shared resources including an Animal Resources Core, a Cell Imaging and Cytometry Core, a Biostatistics Core, a Research Pharmacy, a Clinical Research Core, a Medicinal Chemistry Core, an Analytical Pharmacology Core, a Specimen Accessioning Core, a Tissue Array Core, a cDNA Microarray Core, and Glassware Washing and Common Equipment Cores.  These Cores provide low cost, priority services to the SPORE investigators.  Since the last Prostate Cancer SPORE Program renewal, the Cancer Center has made major investments in the development or improvement of several additional Core resources to support the research activities of SPORE Programs, including:

• An upgrade of the Analytical Pharmacology Core, to support human clinical trials of new agents, featuring the addition of a new data acquisition system (Chromo Perfect Spirit 32 Bit), two Water Alliance HPLC systems, and a Water Micromass LC Benchtop Triple Stage Quadrupole Mass Spectrometer System;
• A Bioinformatics Core, to supplement the Biostastistics Core and meet the growing demand for multidimensional genomic data collection and analysis;
• Construction and staffing of a 2,500 gross ft2 cGMP facility at Johns Hopkins for the manufacture of clinical grade materials for phase I and II clinical trials involving cancer gene therapy and genetic modified cancer cell vaccines;
• Improvements to the Medicinal Chemistry Core, now complete with a nuclear magnetic resonance spectrometer and capable of synthesis of new anti-cancer drugs;
• The targeting of a $5 million gift to SKCCC to increase small animal imaging capabilities for preclinical anti-cancer drug development, and to augment infrastructure for phase 1 clinical trials of new anti-cancer drugs.

In addition, since the last Prostate Cancer SPORE Program renewal, the Brady Urological Institute has also made major investments in the research activities of the SPORE Program, including:

• Purchase of a nanoplotter (GeSiM Nanoplotter 2 – Quantum Analytics) to produce protein arrays (serum, urine, antibodies etc) for analysis of novel biomarkers and targets;
• Increased automation and throughput for serum and urine collection and storage, with improved annotation of a patient information/follow-up for a translational research database;
• Increased proteomics capabilities with the purchase of liquid chromatography system (Biorad) and desingation of dedicated space;
• Lab space (approximately 2,500 ft2) was added in a temporary location (Broadway Research Building) until completion of new laboratory facilities at Park 2;
• Upgrades in laser capture microdissection instruments;
• Added state of the art immunoassay equipment to facilitate the development and implementation of new biomarker assays;
• A commitment of $1,000,000 each year as part of the Patrick C. Walsh Prostate Cancer Research Fund (see below) to supplement Prostate Cancer SPORE investment in Developmental Research Programs, effectively increasing the number of Developmental Research Projects 10-fold.

The Department of Pathology has also committed resources in support of the Prostate Cancer SPORE Program, including:

• The establishment and staffing of a Tissue Microarray Core facility that provides high quality prostate cancer tissue arrays for use in immunohistochemistry studies of new candidate prostate cancer biomarkers and drug targets,
• The assignment of dedicated space in Diagnostic Surgical Pathology for tissue specimen acquisition, processing, and archiving.

(iv) The Patrick C. Walsh Prostate Cancer Research Fund

To ensure that a multi-disciplinary approach to discovery in the field of prostate cancer flourishes, the Johns Hopkins Medical Institutions established The Patrick C. Walsh Prostate Cancer Research Fund to attract and support the best and brightest scientists throughout Johns Hopkins in the fight against prostate cancer.  Since its inception in 1915, the Brady Urological Institute at Johns Hopkins has focused single-mindedly on the study of prostate cancer and the goal of finding better ways to prevent, diagnose, and treat the disease. Over the past 20 years, progress in discovery has skyrocketed and prostate cancer research activities have spread throughout many Departments at Johns Hopkins.  The Patrick C. Walsh Prostate Cancer Research Fund, assembled by the generosity of philanthropic investments and named for the former Brady Urological Institute Director and Department of Urology Chairman, assigns $1,000,000 each year to new pilot projects, intending to attract outstanding scientists from throughout the Johns Hopkins University who bring fresh thinking and new research initiatives.  The pilot project funding activities of the Fund are fully integrated and coordinated with the SPORE Program support of Career Development and Developmental Research.  Each year a request for applications is distributed to all scientists throughout Hopkins, soliciting interest in applying for research funding in the field of prostate cancer.  Application submission involves a dedicated website maintained by the Brady Urological Institute and SKCCC.  The Patrick C. Walsh Prostate Cancer Research Fund applications are subjected to peer review along with the SPORE Career Development and Developmental Research applications, and highly meritorious proposals are funded.  The inaugural round of Patrick C. Walsh Prostate Cancer Research Fund awards were given in the spring of 2005.

(v) Other Institutional Investments in Prostate Cancer Research

The Comprehensive Cancer Center and Brady Urological Institute have also directed a substantial amount of funds to Prostate Cancer SPORE Program investigators.  At the Cancer Center, pilot project funds, with awards in excess of $300,000 each year, are available for SPORE Program investigators.  In addition, a $1.5 million endowment for Prostate Cancer Clinical Investigation has also been established.

(v) Training

The Hematology-Oncology clinical and research fellowship training program supported by the Cancer Center trains 24 physician scientists in any given year.  Dr. William G. Nelson plays a key leadership role in the research training aspects of this program, serving as the Principal Investigator of the Molecular Targets Training Grant (T32 CA09071).  The Department of Urology supports the research training of 2 urology residents each year as well as urology fellows.  At any given time, at least 5 or 6 of these trainees are under the direct supervision of Prostate SPORE Program investigators.

As demonstrated above, the Johns Hopkins University provides considerable support to prostate cancer research and to the Prostate Cancer SPORE Program.  Many of the commitments outlined above, i.e., faculty recruitment, commitment of Core resources, and provision of institutional funds, are ongoing and will continue well into the next project period of the SPORE.  Also, as new needs are identified for the Prostate Cancer SPORE Program, the Johns Hopkins University is committed to providing the funds necessary to accomplish SPORE translational research goals.

(3) Institutional Oversight of the Prostate Cancer SPORE Program

At the SKCCC, the Prostate Cancer SPORE Program is encompassed within a Prostate Cancer Program.  As a formal Cancer Center research program, the Prostate Cancer Program has its scientific progress monitored through peer-review of the Comprehensive Cancer Center Support Grant, and through annual reviews by the SKCCC External Advisory Committee.  In addition, the SKCCC also oversees the research progress of all its SPORE Programs, and identifies SPORE Program research needs, via regular SPORE Program reviews by the Cancer Center Research Council and by the Cancer Center Internal Advisory Committee.  For further focused institutional oversight, the Prostate Cancer SPORE Program management structure (see B. Scientific and Administrative Leadership) features an Internal Oversight Committee, which will meet annually to review SPORE research progress, approve changes in SPORE Program research directions, and consider institutional contributions to accelerate research progress. Dr. Donald S. Coffey, the former Prostate Cancer SPORE Principal Investigator, will Chair the Internal Oversight Committee; Dr. Chi Van Dang, the Vice Dean for Research at the Johns Hopkins University School of Medicine, Dr. Martin D. Abeloff, the Director of the SKCCC, Dr. Alan W. Partin, Chairman of Urology, and Dr. John D. Groopman, Chairman of Environmental Health Sciences at the Bloomberg School of Public Health and Deputy Director of the SKCCC Prevention, will serve as Committee members.

D. Relationship of the Prostate Cancer SPORE to the Sidney Kimmel Comprehensive Cancer Center (SKCCC)

The SKCCC at Johns Hopkins was fully-designated as an NCI Comprehensive Cancer Center in 1976, successfully competing for its first Cancer Center Support Grant in 1978.  The Cancer Center is a Department of the Johns Hopkins University School of Medicine as well as a Center at the Johns Hopkins Hospital, and thus Dr. Martin D. Abeloff, the Cancer Center Director, reports to the Dean of the School of Medicine and CEO of Johns Hopkins Medicine, Dr. Edward Miller.  Dr. Abeloff is also the Oncologist-in-Chief of the Johns Hopkins Hospital.  The SKCCC is comprised of eleven peer-reviewed Research Programs, including a Prostate Cancer Program.  The Johns Hopkins Prostate Cancer SPORE is encompassed within the Prostate Cancer Program, which reached full Program status in 1996.  The Principal Investigator of the Prostate Cancer SPORE, Dr. William G. Nelson, is a senior leader at the SKCCC, reporting directly to the SKCCC Director, Dr. Martin D. Abeloff.  Dr. Nelson is the Director of the Prostate Cancer Program and Associate Cancer Center Director for Translational Research, as well as the Prostate Cancer SPORE Program Principal Investigator, and serves on the SKCCC Executive Committee, the Cancer Center Research Council, along with other Cancer Center Division Directors, Program Leaders, and Principal Investigators of other SPORE Programs, to advise Dr. Abeloff on research directions, faculty recruitment, and allocation of resources at the Cancer Center.  As a formal SKCCC Research Program, the Prostate Cancer Program has its scientific progress monitored through peer-review of the Comprehensive Cancer Center Support Grant and through the annual reviews by the SKCCC External Advisory Committee.  The Prostate Cancer Program was last peer-reviewed in 2005, earning an Outstanding to Excellent rating.  In addition, the SKCCC also oversees the research progress of its SPORE Programs, and identifies SPORE Program research needs, via regular SPORE Program reviews by the Cancer Center Research Council and by the Cancer Center Internal Advisory Committee.  SPORE Program Investigators also have access to Comprehensive Cancer Center Core Resources, including an Analytical Pharmacology Core, a Medicinal Chemistry Core, a GMP facility for manufacture of cell and gene therapy components, a Biostatistics Core, a Bioinformatics Core, a Clinical Research Council (the SKCCC Institutional Review Board for clinical trials/human subjects research), a Clinical Research Office with Data and Safety Monitoring Boards, etc.  To promote collaboration and coordination across academic Departments at Johns Hopkins for the Prostate Cancer SPORE Program, the Co-Principal Investigator of the Prostate Cancer SPORE, Dr. Robert H. Getzenberg, as well as most of the other Prostate Cancer SPORE Investigators, are active members of the SKCCC. 

Although integrated into the SKCCC, the Prostate Cancer SPORE Program also features independent Core Resources that do not duplicate SKCCC Cores.  The SPORE Program Administrative Core supports independent SPORE Program oversight by the Principal Investigator, Co-Principal Investigator, Executive Committee, Internal Oversight Committee, and External Scientific Advisory Board.  The Tissue Archive Cores provides unique services to the SPORE Program.  The Prostate Cancer SPORE Program Clinical Trial/Biostatistics Core augments the Cancer Center Biostatistics Core and Clinical Research resources by directing and supporting dedicated effort of biostatisticians to SPORE Program activities.

Prostate Cancer SPORE Investigators are involved significantly in several Cancer Center activities undertaken to improve translational research:

• Howard-Hopkins Partnership:  The Howard University Cancer Center (HUCC) and the SKCCC have been supported by U54 grant, recently renewed, to support a Partnership between the two Centers targeted at decreasing cancer morbidity and mortality in African-American populations served by the two institutions.  The Partnership builds on collaborative research efforts, and has featured three different collaborative Projects focused on prostate cancer and involving Johns Hopkins Prostate Cancer SPORE investigators: (1) William B. Isaacs (SKCCC)/Richard Kittles (HUCC), “Genetics of Prostate Cancer in African-Americans”; (2) John T. Isaacs (SKCCC)/Oladapo Bakare (HUCC), “Novel Bifunctional Anti-Androgens for Prostate Cancer”; and (3) Samuel R. Denmeade (SKCCC)/Robert L. Copeland (HUCC), “Synthesis and MAPK Kinase Inhibitory Activites In Vitro and In Vivo in Human Prostate Tumors by Imido-Substituted 2-Cloro-1,2-Naphthoquinones”.  Two newly recruited HUCC faculty (joining in the spring of 2007), Drs. Bernard Kwabi-Addo and Karen Hill-Williams, have strong interests in prostate cancer, and will likely join SKCCC collaborators in pursuit of new collaborative research activities in the future.  Dr. William G. Nelson, the Prostate Cancer SPORE Program Principal Investigator, serves as a Co-Principal Investigator of the HUCC/SKCCC Partnership grant with Dr. Martin D. Abeloff, the SKCCC Director. 
• Maryland Cigarette Restitution Fund Research Grant/Prostate Cancer Demonstration Project:  With funds from its settlement with cigarette manufacturers, the State of Maryland has awarded a Cigarette Restitution Fund Grant to the SKCCC to support a number of initiatives.  One major area of focus is a Prostate Cancer Demonstration Project, directed by Dr. Jean G. Ford, newly recruited to Johns Hopkins to build community and health disparities research in cancer.  The Demonstration Project has drawn together a multidisciplinary team of basic and clinical researchers, epidemiologists, and behavioral scientists to create a comprehensive program to target prostate cancer as a major cause of cancer death in African-Americans in Baltimore City and Maryland. Drs. William G. Nelson, Elizabeth A. Platz, and Alan W. Partin, all associated with the Prostate Cancer SPORE Program, help Dr. Ford lead the development of the plans for this Project. 
• Molecular Targets Training Grant (T32 CA09071):  This training programis focused on educating clinical oncology fellows to be translational researchers, supporting fellowship training in studies of genetic and epigenetic alterations in cancer that might serve as new biomarkers for cancer detection and diagnosis and new cancer-specific targets for therapy.  Several Prostate Cancer SPORE Program Investigators serve as faculty mentors for this program.  Dr. William G. Nelson, the SPORE Program Principal Investigator, is the Principal Investigator of the Molecular Targets Training Grant (T32 CA09071).

For further delineation of the relationship of the Johns Hopkins Prostate Cancer SPORE Program to the SKCCC, see attached letter of Institutional Commitment signed by the SPORE Principal Investigator and Co-Principal Investigator, the Cancer Center Director, the Chairman of Urology, and the Dean of the Johns Hopkins University School of Medicine.

E. Cancer Patient Population

The Prostate Cancer Program at the SKCCC conducts periodic reviews of both its prostate cancer patient population and its clinical research portfolio for prostate cancer, with the goal of more effectively achieving translation of basic science discoveries to clinical research opportunities.  Clinical trials emerging from Prostate Cancer SPORE Program Research Projects are assigned the highest priority for study subject enrollment.  Over the past several years, the SKCCC Tumor Registry has recorded an average of ~1360 cases/year of prostate cancer.  The clinical stage distribution of the new cases in the Tumor Registry reflects the national trends for prostate cancer, with most cases (73%) representing American Joint Committee of Cancer (AJCC) Stage II disease.  Given the low stage of disease, young patient population (80% under age 70 years), and the historic strengths of the Department of Urology, over 72% of the new patients opt for surgery as their initial therapy, with over 69.5% of them residing outside of the states of Maryland, Pennsylvania, Virginia, and Delaware.  Of the patients choosing radiation therapy, 85% are over age 70 and/or have prostate cancer with moderate to high grade Gleason scores.  The number of new prostate cancer patients seen by medical oncologists as new cases is somewhat smaller, ~300 cases/year, and includes patients with progressive prostate cancer despite surgery or radiation therapy as well as patients newly presenting to Johns Hopkins. 

Almost all patients visiting Johns Hopkins are enrolled into natural history studies and contribute tissues and other biospecimens, and demographic and clinical information, for future research (see Tissue Archive Core B for a description of this resource).  The Tissue Archive has accumulated prostate tissue specimens from >15,000 radical prostatecomies.  Some 742 curated specimens, well-preserved and with extensive associated clinical data, have been captured in tissue microarrays; >1000 more specimens have been located, analyzed for adequacy of fixation, etc., and will be arranged in tissue microarrays within the next 4-6 months (see Core B).  In conjunction with the Early Detection Research Network (EDRN) biomarker program at Johns Hopkins, directed that Drs. Alan W. Partin and Daniel W. Chan, the Prostate Cancer SPORE Program, during the last funding period, collected and archived 6,200 serum samples from men (81% Caucasian, 13% African American, 4% Asian, and 2% other) with prostate cancer, or undergoing an evaluation for an elevated serum PSA.  Approximately 20% of these patients attended the urology clinic for prostate biopsies, 12% of the men were evaluated for elevated PSA, 61% of the men were new prostate cancer patients, and 7% were scheduled for radical prostatectomy.  This brought the size of the serum specimen collection to ~12,000.  In addition to serum, the joint SPORE/EDRN collection activities also began to collect urine specimens, adding 248 such specimens in 2006.  The collected and processed biospecimens, including serum, raw urine aliquots, soluble urine fractions, and pelleted urine sediment, are stored and inventory-managed utilizing data matrix barcoding technology.  A CODESOFT 7.1 label design software and a Brady CR2 barcode reader interact with the sample database and permit tracking of sample quantities in real time as well as study-specific sample utilization.

With the recognition that such a large fraction of prostate cancer cases first present to Johns Hopkins with limited stage disease to urologists, this group has been targeted for key prostate cancer prevention translational research clinical trials.  For example, over the last 3-5 years, three clinical trial protocols have been open for men with localized prostate cancer who are about to undergo prostatectomy, one trial featuring a brief exposure (4-6 weeks) to celecoxib, another a brief exposure to different tocopherol preparations, and a third intake of sulforaphane, a trial prompted, though not funded, by a current SPORE Program Research Project.  In each study, the key translational research endpoint was a biomarker of chemoprevention activity assayable in prostate tissues recovered after radical prostatectomy.  All three studies required active participation from Prostate Cancer Program urologists: 140 men were enrolled in these studies in the last 3-5 years.  Accrual to the celecoxib trial, a randomized, placebo-controlled, double-blinded study, which was undertaken with an NCI contract with the Division of Cancer Prevention (DCP), was completed by December 2004, ahead of other contract awardees for similar trials at other institutions.  Most of the endpoint biomarker analyses for this study have also been completed; however, the study blind has not yet been broken awaiting completion of all laboratory biomarker assays.   

In addition to biospecimen acquisition, clinical data from men undergoing radical prostatectomy at Johns Hopkins are entered into a Health Insurance Portability and Accountability Act (HIPAA)-compliant database for future analyses of the extent/severity of prostate cancer at presentation and treatment outcome (time-to-recurrence after surgery, survival, etc.).  Using this database, the well-known and widely-used “Partin Tables” and “Pound Tables” were created; each of the predictive tools is routinely updated as the database captures more and more prostate cancer cases.  The database has also permitted the generation of a model to predict risk for cancer recurrence (a rising serum PSA) after prostatectomy that has been successfully applied to a pilot adjuvant chemotherapy trial led by SKCCC Prostate Cancer Program investigators.  The study sought to test the feasibility, as well as the impact, of six months of adjuvant docetaxel chemotherapy given to men with prostate cancer considered at high risk for relapse after surgery based on the predictive model (defining risks groups via a factor termed Rw).  Seven collaborating institutions enrolled patients into this study over an 18 month period, accruing 77 study subjects, with SKCCC Prostate Cancer Program investigators leading all institutions in numbers of subjects enrolled.  The results of the trial demonstrated the feasibility of adjuvant chemotherapy after radical prostatectomy for prostate cancer, laying the foundation for a large multi-institutional and multi-national Phase 3 adjuvant chemotherapy study, written and led by Dr. Mario A. Eisenberger, which will define the state-of-the-art.  Men with prostate cancer who suffer recurrence after local therapy are accrued to the “Identifying Prostate Cancer Genes” study, seeking to ascertain whether germline polymorphic variants of key genes might affect prostate cancer progression; some 280 men/yr at SKCCC enroll in this study.  

The largest population of men presenting to medical oncologists have a rising serum PSA after local therapy, as the only manifestation of prostate cancer (Class D, see below).  Most of these men desire alternatives to the early use of androgen deprivation therapy.  As a consequence, a number of clinical studies have targeted this patient population, including the first-in-man study of genetically-modified prostate cancer cell vaccines sponsored by the SPORE Program, an investigator-initiated trial of marimistat, given at three different doses, an Abbott Laboratories-sponsored study of atrasentan, and a Prostate Cancer Foundation (PCF)-funded collaborative trial of rapidly cycling chemotherapy/hormonal therapy.  The atrasentan trial enrolled 200 patients at select sites throughout the US, with SKCCC accruing nearly 10% of study subjects, reflecting the significant early role of Johns Hopkins SPORE Program investigators in the identification of this pathway in prostate cancer and in the development of this agent.  The PCF study was jointly written by SKCCC Prostate Cancer Program investigators and investigators from Memorial Sloan-Kettering Cancer Center (MSKCC).  To date, accrual to the trial has been completed (a year earlier than anticipated) and the feasibility of the rapidly cycling chemohormonal treatment approach has been demonstrated; final assessments of the duration of serum PSA declines in response to treatment are pending.  In this trial, men with physiological androgen levels had lower clearance rates of docetaxel than men subjected to androgen-deprivation therapy: almost 90% of men in the trial had Grade 3 or Grade 4 neutropenia, as compared some 15-30% of men in the TAX-327 Study of men were found to have neutropenia.  These findings suggest that oncologists may be under-dosing men androgen-independent prostate cancer when giving docetaxel.  Further pharmacological studies of the mechanisms for the apparent androgen-dependence of docetaxel clearance are underway: an amended protocol addressing these issues and further refining dose/schedule of chemohormonal therapy recently opened and is accruing subjects briskly.  With the rapid accrual rate to the collaborative PCF study, a new protocol is planned looking at serum PSA changes attributable to treatment with revlimid in the same patient population.

The SKCCC Prostate Cancer clinical trials portfolio for advanced prostate cancer is multi-layered.  Many men can participate in 2-4 prostate cancer-specific trials, depending on their performance status and state of disease.  For example, a man could enroll on a Phase 2 study of amonafide, and if he suffers cancer progression, he could then participate in a trial of docetaxel and samarium.  If his cancer progresses despite this treatment approach, he would be eligible for participation in a Phase 1 study of mitoxantrone and OSI-461, followed by a clinical trial of treatment with remicade if he has cancer-related pain.  Many men choose treatments as part of non-prostate cancer-restricted Phase 1 trials: as an example, men with prostate cancer are considered for treatment with combinations of MS-275 and isotretrinoin based on SKCCC Prostate Cancer SPORE Program laboratory research findings of promise to this combination.

In summary, men with prostate cancer seen at SKCCC have been categorized into 9 different disease states/treatment classes.  The Prostate Cancer Program strives to have clinical trials open, particularly trials emerging from SPORE translational research efforts, for each of these groups so that most men visiting Johns Hopkins will be offered participation in a clinical study if he meets eligibility requirements and lives close enough to SKCCC to participate.  The prostate cancer clinical trials group meets twice monthly (the Stine Conference) to monitor accrual ongoing studies, and to foresee clinical trial closures/completions, to reduce gaps in the availability of trials for any disease state.  The disease states/treatment classes are as follows:

• Class A:  Pre-surgery/Pre-XRT
• Class B: High risk for relapse after radical prostatectomy
• Class C: High risk for relapse after radiation
• Class D: Rising serum PSA after local therapy, hormone-naive
• Class E: Rising serum PSA on hormonal therapy, no evidence of metastasis
• Class F: Rising serum PSA, metastatic, chemotherapy-naive
• Class G: Hormone-refractory, prior chemotherapy for metastatic disease
• Class H: Hormone-refractory, multiple prior therapies
• Class I: Supportive care/ Phase 1 studies

The SKCCC has supported expansion of the prostate cancer clinical trials unit over the last couple of years, with a focus on completing SPORE Program translational research studies and on facilitating clinical research activities at the sites where men with prostate cancer are seen and treated.  At this time, the clinical trials unit consists of 5 research nurses, 5 data managers, and 2 nurse practitioners (who assist in protocol development and regulatory affairs).  This group is not only responsible for clinical trials in prostate cancer but also the other genitourinary malignancies.   The clinical trials group meets weekly to review all patients seen the previous week and the upcoming week to discuss each patient’s potential to participate in our ongoing clinical trials.  This group meets every other week (as part of the Stine Conference) to review new studies, to evaluate progress of ongoing trials, and to review data and prepare publications from completed trials.  Increasing attention has been afforded reviewing clinical trial eligibility requirements as potential barriers to accrual, particularly to the accrual of minority subjects.  Hopefully, as the SKCCC prostate cancer patient population is better understood, the reasons some men with prostate cancer are unable to participate in the menu of available clinical trials will become more apparent.

Overall, there has been an increase in the yearly accruals to therapeutic clinical trials for prostate cancer from ~6% in 2002 to >10% in ensuing years.  This has been the result of the assembly of a well-functioning clinical research team and the tailoring of the portfolio of clinical trials to the prostate cancer patient population.  The primary priority is assigned translational research trials emanating from the SPORE Program, with secondary priority given other investigator-initiated and cooperative group studies.  Many of the industry-sponsored studies undertaken recently have been selected because of the direct involvement in defining the target, the agent, and /or the clinical trial design.  With key Prostate Cancer Program personnel in positions of leadership in the Departments of Urology and of Radiation Oncology and Molecular Radiation Sciences, the Program is poised to further increase the number of trials and subjects enrolled to therapeutic trials.  For men undergoing prostatectomy, CALGB 90203 has been activated, continuing the chemoprevention biomarker studies pre-prostatectomy with agents such as broccoli sprouts steeped in hot water (from a SPORE Research Project), considering testing HDAC and mTOR inhibitors, and steering men at high risk of relapse to the Phase 3 adjuvant docetaxel chemotherapy trial, to be led internationally by Dr. Eisenberger.  For men selecting radiation as primary therapy, a new Phase 2 study evaluating the benefits of tomotherapy has been launched.  For men at high-risk for prostate cancer progression, new clinical studies will test combinations of radiation therapy and treatment with docetaxel chemotherapy or with replication-restricted, oncolytic adenoviruses (from the SPORE Program).

Specific efforts to increase minority participation in Prostate Cancer Program clinical trials are underway as well.  Increased prostate cancer screening and outreach activities, targeting minority residents of Baltimore City, have been undertaken as part of the Prostate Cancer Demonstration Project, led by Dr. Jean G. Ford, and funded by the State of Maryland Cigarette Restitution Fund.  To steer minority men with prostate cancer diagnoses toward state-of-the-art treatment and facilitate participation in clinical trials, Dr. Ford has initiated a Patient Navigator program, featuring a nurse educator.  The Prostate Cancer Program has held community physician dinners to increase awareness of prostate cancer clinical trial options at the SKCCC among referring physicians.  In the last three years, the Prostate Cancer Program also co-sponsored, along with the University of Maryland, a regional prostate cancer symposium entitled “New Perspectives in Prostate Cancer.”  The Symposium has attracted more than 100 local/regional urologists, radiation oncologists, and medical oncologists each year.  The Clinical Trial Information Specialist hired in to the SKCCC Referral Office has been highly successful in recruiting subjects for the prostate cancer clinical trials.  Prostate cancer patients that are scheduled for SKCCC clinic visits appear more likely to participate in clinical trials, when presented the variety and number of clinical trial options available, than many other solid tumor patients. 

F.  Scientific Integration of the Johns Hopkins Prostate Cancer SPORE – Interactions and Collaborations

(1) Johns Hopkins Prostate Cancer SPORE Translational Research Portfolio

The Johns Hopkins Prostate Cancer SPORE aims to apply insights gleaned from prostate cancer molecular biology to ultimately improve the screening, early detection, diagnosis, prevention, and treatment of prostate cancer.  Of the six Research Projects proposed, each targets a translational research hypothesis for testing in clinical trials or in population studies, each is directed by two Co-Principal Investigators, one with expertise in prostate cancer biology (“basic”), and the other with expertise in population studies or in clinical trials of new cancer treatments (“applied”), and each makes use of one or more Core Resources. 

Research Projects #1, #2, #3 and #4 all focus on new approaches to prostate cancer treatment; Research Projects #1 and #3 feature unconventional treatment approaches, targeted delivery of interfering RNAs with aptamers and vaccination with modified Listeria organisms, while research Projects #2 and #4 aim to develop new “small” molecule treatments.  Of course, “small” molecule radiation sensitizers have been commonly used in the treatment of gastrointestinal, gynecological, and aerodigestive tumors, but are limited in that the drugs lack specificity: normal cells and tissues tend to be sensitized as much as the cancer cells and tissues.  For Research Project #1, targeted delivery, made possible by aptamers that are selectively bound and internalized by prostate cancer cells, is exploited in the design of selective radiosensitizers.  The hypothesis to be tested is that the therapeutic index for local treatment of prostate cancer can be improved by selectively sensitizing prostatic cancer cells to ionizing radiation using targeted delivery of inhibitory RNAs that disrupt the expression of radiation repair proteins.  The aptamer to be used for targeting, xPSM-A10, has been previously shown to deliver interfering RNAs efficaciously and selectively to prostate tumor cells in vivo.  Research Project #2 aims to build on experiences from a Research Project conducted during the last SPORE funding period, featuring the discovery and development of prostate cancer pro-drugs activated by PSA, to target PSA itself for inhibition to attenuate prostate cancer growth, progression, and/or metastasis.  Plans are to synthesize monocyclic beta-lactam inhibitors of PSA and other prostate cancer proteases, introduce these inhibitors into preclinical models of biovailability, pharmacokinetics, safety, and efficacy against prostate cancer, and then to simulataneously develop serum PSA activity assays that can be used as pharmacodynamic endpoint biomarkers for human clinical trials.  For Research Project #3, previous successes with genetically-modified prostate cancer cell vaccines, now in pivotal phase 3 FDA registration trials, have led to new cancer immunology discoveries that immunological “checkpoints” limiting autoimmunity may also limit cancer immunotherapy.  As such Project #3 aims to develop an approach to exploit synergy between therapeutic blockade of the checkpoint mediated by B7-H1/PD-1 and vaccination using an attenuated Listeria strain genetically-modified to express tumor-associated antigens.  In the laboratory, this combination treatment appeared unique in its ability to break immune tolerance in tumor-bearing hosts, and to restore cytolytic function to tumor-specific CD8+ T-cells.  To test this possibly synergistic combination, the immunogenicity, safety and tolerability of immunotherapy for prostate cancer, using monoclonal antibody blocking the inhibitory B7-H1/ PD-1 axis either alone, or in combination with an attenuated Listeria strain expressing Prostate Stem Cell Antigen (PSCA), will be evaluated in a phase 1/2 clinical trial (n = 42) enrolling men with high-risk prostate cancer about to undergo radiation therapy.  Trial endpoints will include determining whether treatment causes infiltration of the prostate gland with pro-inflammatory immune cells and ascertaining whether any pre-treatment immunological variables can predict treatment outcome.  Research Project #4 aims to accelerate the development of histone deacetylase (HDAC) inhibitors for prostate cancer by considering novel combinations of the inhibitors with other agents targeting cancer-associated pathogenic pathways, such as cell survival and tumor angiogenesis.  Plans are to identify specific gene pathways, proteins, and transcriptional factors interacting with different HDAC isoenzymes to determine the potential promise of HDAC isoenzyme-selective drugs, to discover and develop novel combinations of HDAC inhibitors and other agents in preclinical models, and to carry the most promising combinations into clinical trials.  Each of the Research Projects will make use of the Tissue Archive Core (B) and Biostatistics Core (C). 

One of the challenges to have emerged from the PSA screening era for prostate cancer is the likelihood that as many as 20% or more of men diagnosed with prostate cancer may be subjected to overtreatment of the disease.  The final two Research Projects focus on new molecular biomarkers, to be tested in population studies, which can predict the aggressiveness of localized prostate cancer, helping to stratify men for prostate cancer treatment.  Research Project #5 builds on the discovery, made as part of SPORE Program research, that prostate cancer cells characteristically contain somatic epigenetic defects, recognizable at the earliest stages of carcinogenesis.  Using newly developed 5-meCpG capture technology, genome-wide assay screens of abnormal DNA methylation changes in prostate cancer cells will be analyzed for candidate tissue biomarkers of prostate cancer behavior.  Biomarkers capable of discriminating aggressive prostate cancer will be validated in population studies using cohorts of men at Johns Hopkins and at the Harvard School of Public Health, an example of collaboration between SPOREs at the two institutions.  Research Project #6 will test the possibility that EPCA-2, a newly discovered serum protein biomarker for prostate cancer, can serve to discriminate aggressive from non-aggressive prostate cancer.  To test this hypothesis, a multi-institutional approach is planned, featuring interactions/collaborations with other Prostate Cancer SPORE Programs.  The propensity for serum EPCA-2 to differ between men with prostate cancer and a Gleason score 6 and 7 versus a Gleason score of 8-10 will be tested in cohorts of men from the Johns Hopkins Hospital patients as well as from other SPOREs.  In addition, for men with prostate cancer and a Gleason score of 7, the association of serum EPCA-2 and prostate cancer recurrence after initial therapy will be determined using cohorts of men with prostate cancer and a minimum of 10 years of follow-up, available at Johns Hopkins and at the Dana-Farber Cancer Institute SPORE Program.  Finally, the function(s) of EPCA-2 during the pathogenesis of prostate cancer, as well as the means by which the protein appears in the serum, will be studied.  Of significance, not only will Research Projects #5 and #6 will make use of both the Tissue Archive Core (B) and the Biostatistics Core (C), but both Projects will use the Administrative Core (A) to help manage the planned inter-SPORE collaborative ventures.

(2) Johns Hopkins Prostate Cancer SPORE Core Resources

Core Resources will support the Research Project portfolio as described above, and will develop new capabilities that facilitate rapid translation of new prostate cancer molecular biology insights into new hypotheses for testing in population studies or in human clinical trials.  An Administrative Core (Core A) will coordinate oversight over Prostate Cancer SPORE Program activities, facilitate collaborations between the Johns Hopkins Prostate Cancer SPORE Program and SPORE Programs at other academic centers, and orchestrate responses to new initiatives from the NCI.  A Tissue Archive Core (Core B) has assembled a large prostate cancer tissue bank that has already been used as the basis for key discoveries concerning somatic genome abnormalities in prostate cancer cells, changes in gene expression associated with prostatic carcinogenesis, and new prostate cancer tissue biomarkers.  This Core has established a tissue microarray capability to accelerate translational research efforts that has become the model for all SPORE Programs at Johns Hopkins.  The Tissue Archive Core also features a robust immunohistochemical staining capability.  In addition, the Directors of the Johns Hopkins Prostate Cancer SPORE Program Tissue Archive Core have developed extensive collaborative interactions with Directors of Tissue Archives associated with other Prostate Cancer SPORE Programs.  Finally, a Biostatistics Core (Core C), staffed with epidemiologists and clinical trial biostatisticians, will oversee all biostatistics associated with the SPORE, participating in the designs of preclinical model studies and clinical trials for SPORE investigators, and in the analysis of all experimental data collected as part of SPORE Research Projects.  This Core will complement the SKCCC Biostatistics and Bioinformatics Shared Resources; the SPORE will directly support significant effort by biostatisticians, coordinating biostatistics activities at the SKCCC and in other academic Departments.

G. Translational Research Objectives

(1) Promoting Translation of New Basic Research Findings “to Test the Feasibility of Cancer-Relevant Interventions in Humans and to Determine the Biological Basis for Observations made in Individuals with Cancer or in Populations at Risk for Cancer”

The Johns Hopkins Prostate Cancer SPORE Program is dedicated the reduction of prostate cancer incidence and mortality via the focused pursuit of translational research in prostate cancer.  The NCI has defined translational research for the SPORE program as “[using] the knowledge of human biology to develop and test the feasibility of cancer-relevant interventions in humans and/or [determining] the biological basis for observations made in individuals with cancer or in populations at risk for cancer.”  To promote translational research of this type that can succeed at reducing prostate cancer incidence and mortality, the Johns Hopkins Prostate Cancer SPORE Program has emphasized several thematic approaches:

(i) The Development of a Highly-Interactive Multi-Disciplinary Team to Study Prostate Cancer.  To accomplish translational research objectives, the contributions of molecular biologists (Drs. Robert H. Getzenberg, Shawn E. Lupold, John T. Isaacs, and Srinivasan Yegnasubramanian) and medical oncologists (Drs. Charles G. Drake and Roberto Pili), serving as “basic” scientists, have been coordinated with contributions of radiation oncologists (Dr. Theodore L. DeWeese), urologists (Dr. Alan W. Partin), and medical oncologists (Drs. Samuel R. Denmeade, William G. Nelson, and Michael A. Carducci), serving as “applied” scientists, and supported by epidemiologists (Drs. Bruce J. Trock and Elizabeth A. Platz), pathologists (Drs. Angelo M. De Marzo, George J. Netto et al.), and a variety of other experts.  This spirit and culture of collaboration across scientific disciplines and academic Departments was established when the Prostate Cancer SPORE Program was initially funded, and has persisted despite changes in personnel.  Each of the SPORE Program Research Projects and Core Resources for this competitive renewal application has been developed via joint contributions between “basic” and “applied” scientists.  With these highly-interactive multi-disciplinary Research Project teams, the translation of new prostate cancer molecular biology insights to new population studies or clinical trials should be maximally accelerated.

(ii) The Use of Human Serum, Blood, Prostate Tissues, and Cell Lines in Research Projects.  All of the SPORE Program Research Projects and Core Resources emphasize the study of human prostate cancer, using laboratory animals only as models of human disease that permit more efficient translation of prostate cancer molecular biology insights to hypotheses for testing in human population studies or clinical trials.  A specific Core Resource for Tissue Archiving (Core B) has been developed to facilitate the use of human materials for translational research effort.

(iii) The Development of New Approaches to Prostate Cancer Treatment.  New prostate cancer treatments are needed.  Four Research Projects (#1, #2, #3, and #4) have been proposed that directly feature new prostate cancer treatments, ranging from aptamer-targeted agents, to prostate-specific pro-drug activation therapy, to improved prostate cancer immunotherapy, to “silenced” gene re-expression therapy.  The ultimate goal of each of these Research Projects is the generation of specific hypotheses for human clinical trials, initiating or forwarding the development of new prostate cancer treatments.

(iv) The Discovery of New Epigenetic Markers of Prostate Cancer in Population Studies.  To best exploit the findings of the Human Genome Project for prostate cancer, epigenetic as well as genetic markers associated with prostate cancer need to be discovered.  Such markers will permit the discrimination of men at high prostate cancer risk for intensive prostate cancer screening, for participation in clinical trials of new prostate prevention agents, and for stratification into risk groups to for optimal treatments.  The epigenetics studies proposed as part of the SPORE Program Research Project (#5) portfolio, bringing together prostate cancer molecular biologists and epidemiologists, will discover new molecular biomarkers of prostate cancer to improve prostate cancer diagnosis, detection, and risk stratification.

(v) Application of New Serum Biomarkers of Prostate Cancer to Improve Prostate Cancer Diagnosis and Detection.  Serum PSA testing has revolutionized prostate cancer care in the past tow decades.  Nonetheless, the screening, diagnosis, and detection of prostate cancer can still be improved.  New proteomics approaches to the discovery of serum prostate cancer biomarkers has provided the promise of more sensitive and more specific blood tests to aid in prostate cancer detection and diagnosis.  The development of such approaches, as proposed in the SPORE Program Research Project (#6) portfolio, will be a focus of the SPORE in the next funding cycle.

(2) Use of Developmental Research Funds to Explore Innovative Research Ideas. 

The Developmental Research activities of the Prostate Cancer SPORE Program have been strategically targeted to exploit new research opportunities and to build new prostate cancer research capabilities in key areas.  For example, past Developmental Research support has been targeted at establishing new opportunities for prostate cancer population studies via funding of epidemiology studies conducted by Dr. Kathy Helzlsouer.  These initial studies not only have led to publications, but have grown into a vibrant prostate cancer epidemiology effort, involving Drs. Bruce J. Trock and Elizabeth A. Platz, that has become internationally recognized.  As another example, Developmental Research support was provided to Dr. Paul T’so for early feasibility studies of a technique for isolating prostate cancer cells from the peripheral venous circulation of men with prostate cancer.  The results of these studies not only have led to publications, but have led to the founding of a company, Cell Works, Inc., to further develop this technique for prostate cancer diagnosis, prognosis, and treatment monitoring.  As a final example, Developmental Research funds were awarded to Dr. John T. Isaacs for early studies of pro-drugs activated by prostate-specific enzymes as candidate prostate cancer treatments.  These early studies have blossomed into a full Research Project.  Future plans for the Prostate Cancer SPORE Program Developmental Research activities will be to continue to identify and support key opportunities for new translational research enterprises.  Two Developmental Research Projects are included in the current SPORE Program competitive renewal application.  One Project targets the new finding that the nuclear factor erythroid-related factor 2 (NRF2)/Kelch-like ECH-associated protein-1 (KEAP1) pathway, which controls expression of toxin metabolizing genes, might be constitutively activated in many prostate cancers, as 3 of 4 prostate cancer cell lines have been found to have KEAP1 mutations promoting relentless NRF2 trans-activation of target genes).  The other Project features a clinical study of the effect of antibiotic intake on serum PSA values in men subjected to prostate biopsy procedures.  These Developmental Research Projects are greatly augmented by a large number of Projects supported by the Patrick C. Walsh Prostate Cancer Research Fund to form a robust pipeline for future translation into new approaches to prostate cancer screening, diagnosis, detection, prevention, and treatment. 

H. Planning and Evaluation Activities

(1) Monitoring SPORE Research Progress, Identifying New Translational Research Opportunities, Termination of Research Projects not Achieving Translational Research Objectives

The progress of each SPORE Program Research Project, Developmental Research Project, and Career Development Project, as well as the effectiveness of each Core Resource, will be evaluated periodically by the Executive Committee, at its monthly meetings, by the External Scientific Advisory Board, at its yearly meetings, and by the Internal Oversight Committee, at its yearly meetings.  At each monthly Executive Committee meetings, two Research Projects will be fully reviewed, ensuring 2-3 reviews of each Research Project every year.  Overall scientific productivity and progress toward translational research objectives will be evaluated in these meetings.  If inadequate scientific progress has been made, the Executive Committee will consider all relevant circumstances, seek input from key members of the External Advisory Board, and then prepare a report containing possible plans of action and detailing any consensus reached.  The Principal Investigator and Co-Principal Investigator will then propose a specific plan of action, including discontinuing funding for the Project, conditionally continuing funding for the Project pending adherence to specific research milestones, or continuing funding for the Project pending submission of a research proposal for funding by another mechanism (N.I.H. R01, Department of Defense, etc.).  This plan of action will be subject to review and approval by the Internal Oversight Committee.  The progress of each SPORE Program Research Project, Developmental Research Project, and Career Development Project, as well as the effectiveness of each Core Resource, will also be evaluated by External Scientific Advisory Board at its annual meeting, where each of the SPORE Program investigators will present summaries of their research.  The External Scientific Advisory Board will assist the SPORE Program Principal Investigator and Co-Principal Investigator in preparing a Yearly Progress Report for submission to the Internal Oversight Committee.  The External Scientific Advisory Board may also make recommendations for discontinuing funding for specific Research Projects, for changing the allocation of SPORE funds to exploit critical new translational research opportunities, and for creating new Research Projects out of Developmental Research Projects.  These recommendations will be considered by the Executive Committee, which will prepare a report detailing possible plans of action as above, and the Principal Investigator and Co-Principal Investigator will then propose a specific plan of action, subject to review and approval by the Internal Oversight Committee.  Approved plans will be implemented by the Principal Investigator and the Executive Committee.

As an example of this approach in action, in preparation for submission of this revised competitive renewal Prostate Cancer SPORE Program proposal, the Principal Investigator, Dr. Nelson, and the Co-Principal Investigator, Dr. Getzenberg, considered the current portfolio of Research Projects and determined that each of the Projects would progress to completion and/or productive failure (ascertaining that further translation should not be undertaken) by the spring of 2008.  As such, they went on to prioritize a new SPORE Program portfolio of Research Projects along with the Executive Committee after considering peer-review critiques and plans for Research Project modifications and revisions.  Using this process, the six Research Projects were selected for the current application from an initial pool of more than twice that many. 

If new translational research opportunities arise, either from scientific progress as part of the Johns Hopkins Prostate Cancer SPORE Program Research Projects, Developmental Research Projects, or Career Development Projects, or from the Patrick C. Walsh Prostate Cancer Research Fund, or from scientific progress elsewhere, the creation of new Research Projects or new Developmental Research Projects will be considered by the Executive Committee and the External Scientific Advisory Board.  The Executive Committee will not only be responsible for monitoring progress of SPORE Projects, but will also be responsible for soliciting and reviewing new Developmental Research Projects and Career Development Projects every two years.  The Executive Committee will also consider all initiatives from the NCI.  With these responsibilities, the Executive Committee, with members from several key academic Departments at Johns Hopkins, is well-positioned to consider new research directions and to develop plans of action to exploit these new opportunities. The External Scientific Advisory Board, with expertise in several critical research areas, can provide specific input to Executive Committee deliberations.  When plans of action have been developed, the SPORE Program Principal Investigator and Co-Principal Investigator will propose a specific plan, subject to the review and approval of the Internal Oversight Committee.  Approved plans will be implemented by Principal Investigator and the Executive Committee.

When the Principal Investigator and Co-Principal Investigator meet each year with the Internal Oversight Committee, they will present a report that contains minutes of Executive Committee Meetings, recommendations from the External Scientific Advisory Board, and any new proposals for discontinuing Research Projects, for creating new Research Projects, and for new Developmental Research Projects and Career Development Projects.  This report will form the basis for strategic planning by the Principal Investigator, Co-Principal Investigator, and Internal Oversight Committee.  The Internal Oversight Committee will help not only by reviewing and approving proposals by the Principal Investigator and Co-Principal Investigator, but also by considering how allocation of institutional resources can best be used to forward SPORE Program translational research objectives.             

(2) Annual SPORE Investigator Workshop

The Johns Hopkins Prostate Cancer SPORE Program Principal Investigator, Co-Principal Investigator, Research Project leaders, Core Resource Directors, Developmental Research Project leaders, and Career Development Project leaders, will attend the annual NCI SPORE Program Workshop each summer.  At the Workshop, exciting new progress from the Research Projects will be presented, as well as new difficulties or challenges arising during the pursuit of translational research objectives.  Key personnel in areas of translational research shared among several SPORE Programs, such as cancer immunotherapy, gene therapy, cancer prevention, tissue archiving, etc., will meet with personnel from the other SPORE Programs to discover new opportunities for collaboration, to identify shared hindrances, and to standardize translational research approaches if appropriate.  The Principal Investigator and Co-Principal Investigator will attend the SPORE Program Directors meeting at the end of the Workshop to further consider shared opportunities and challenges.  After the SPORE Workshop has been completed, the Executive Committee will solicit specific input from each of Research Project leaders, Core Resource Directors, Developmental Research Project leaders, and Career Development Project leaders, and incorporate this input into its strategic planning activities.   

I. Collaboration

The Johns Hopkins Prostate Cancer SPORE is committed to engaging in productive collaborations between other SPORE Programs, other NCI-funded Programs, and other institutions, to forward its translational research objectives.  In fact two of the proposed Research Projects for the current competitive renewal application feature collaborations with investigators at other Prostate Cancer SPORE-funded institutions.  Over the past SPORE funding period, Johns Hopkins SPORE investigators have not only been active participants, but leaders of major inter-SPORE initiatives.  In recognition of the importance of these activities to best accelerate translational research progress, Dr. Bruce J. Trock, an epidemiologist and biostatistician with more than 20 years of experience in cancer research, has been designated the Associate Director of the Johns Hopkins SPORE for inter-SPORE interactions.  Already the Director of the Division of Epidemiology of the Brady Urological Institute, Dr. Trock has served as the Co-Director of the Biostatistics Core for the SPORE during its current grant cycle.  He has also provided epidemiologic design and biostatistical support to the Johns Hopkins Molecular Imaging Trial Center, and to the Early Detection Research Network validation trial “Bladder Cancer Microsatellite Analysis of Urinary Sediment.”  In these roles as in previous efforts, he has gained extensive experience in integrating basic and clinical components of multi-disciplinary translational studies.  An expert on biomarkers, clinical outcomes and etiology of prostate and breast cancers, and Dr. Trock is the author or a co-author of more than 95 peer-reviewed publications. 

Dr. Trock has also served as the Principal Investigator of the major inter-SPORE collaborative Project, the Inter-SPORE Prostate Biomarkers Study (IPBS), bringing together all 11 Prostate Cancer SPORE institutions to conduct a rigorous prospective evaluation of 5 promising prognostic biomarkers.  This study was conceived by Drs. Trock, Timothy C. Thompson (Baylor), Mark A. Rubin (Harvard) and others after the NCI requested the Prostate Cancer SPOREs to develop a study to overcome barriers that have prevented translation of molecular biomarkers to the clinic.  The rationale for the study is that the failure to translate biomarkers to the clinic is greatly affected by inconsistent results among studies of the same biomarker, lack of standardization of methods or control for sources of variability, and lack of rigorous prospective design with adequate sample size, statistical analysis and control of confounding.  A consensus panel convened by the Institute of Medicine reached this same conclusion 3 years after the IPBS was conceived.  The IPBS will address this with a prospective study of 700 men receiving primary surgery or radiotherapy for prostate cancer with a moderate risk of recurrence (5-year recurrence free probability of 60-85% by Kattan nomogram).  Five biomarkers will be measured on preoperative biopsy specimens (8q24, p27, ki-67, caveolin-1) or serum (hK2), and correlated with biochemical recurrence (endpoint for initial 5 years of study) and ultimately PSA doubling time and response to therapy for patients who go on to clinical trials (follow-up beyond 5 years).  The biomarkers were selected from among a large number of candidates proposed by SPORE scientists, based on a meta-analysis of each marker performed by Dr. Trock, and an “R01-style” review by 2 reviewers for each marker proposal.  The meta-analysis identified biomarkers for which there were already several retrospective studies suggesting independent prognostic value in multivariable analyses.  Despite the fact that several of these biomarkers are well-known, they have never been tested in a rigorous prospective study, while many newer “sexier” biomarkers do not yet have adequate data from retrospective studies suggesting independent prognostic value. 

A key component of the IPBS is to standardize methods wherever possible, and to carefully annotate pre-analytic sources of variation in specimen handling and processing so that their influence on biomarker results can be accounted for.  An initial pilot study conducted as part of the IPBS by Drs. Samson W. Fine (Memorial Sloan-Kettering), Trock, and Angelo M. DeMarzo demonstrated that variation in biopsy processing protocols among the SPOREs contributed to variation in staining of commonly measured biomarkers such as AMACR.  In addition to evaluating prognosis, he study will also collect frozen biopsies from surgical specimens from an additional 100 patients to conduct expression microarray and array comparative genome hybridization (CGH) discovery studies.  Lastly, the IPBS establishes an infrastructure for rigorous sample collection and annotation that will incorporate cumulative biomarker results and provide a dynamic resource for evaluating future biomarkers across SPORE institutions.  Dr. Trock was instrumental in designing the IPBS, obtaining consensus and commitment among all of the SPOREs, working with NCI to obtain funding through the SPORE Supplement mechanism, and developing a parallel collaboration with the NCI CaBIG Program to develop a flexible bioinformatics system to link the SPOREs in this study.  He continues to lead this first-ever collaboration among all 11 Prostate Cancer SPOREs.

With this track record of success, Dr. Trock is the ideal candidate to facilitate and manage what should become a broad portfolio of inter-SPORE collaborations.

J. Intellectual Property Management Plan

The Johns Hopkins University School of Medicine, through its dedicated Office of Tecnhology Transfer, etc., has protected, and will continue to protect the intellectual property rights of SPORE Program investigators in such a way that any agreements with commercial organizations do not compromise the ability of the investigators to pursue SPORE-related research, make use of SPORE resources, and enter into collaborations with other researchers.  The SPORE Program will manage its interactions with commercial organizations in such a way as not to restrict the ability of SPORE Program investigators to receive and disseminate research materials to and from the general scientific community.  In any interactions with commercial entities involving sponsored research agreements, the SPORE Program will comply with the requirements of the Bayh-Dole Act of the National Institutes of Health upholding basic principals of academic freedom.

The Johns Hopkins University Office of Technology Transfer (JHTT) was created in July 2001 through the consolidation of the Office of Technology Transfer, Homewood campus and the office of Licensing and Business Development (previously known as the Office of Technology Licensing), at the School of Medicine.  The JHTT staff works closely with Johns Hopkins researchers to identify patentable and copyrightable inventions and tangible research properties that may ultimately become commercial products and services. The office promotes and supports the University's research enterprise through licensing the University's technologies, facilitating collaborations between researchers, companies and entrepreneurs interested in developing our innovations and returning a portion of the revenue to our laboratories.  JHTT acts as a point of contact for industry and entrepreneurs wishing to access the University’s intellectual and tangible property.  JHTT actively seeks and nurtures contacts with national and international companies that are capable of developing and commercializing innovations for the public good.

Table 6.  Patents Awarded to Johns Hopkins and SPORE Program Investigators.

K. Data Management

The SKCCC supports both Biostatistics and Bioinformatics Shared Resources to meet the information science and data analysis demands of research efforts its faculty.  These Shared Resources will be available to supplement biostatistics, bioinformatics, and epidemiology capabilities dedicated to the Prostate Cancer SPORE and provided by SPORE Core B.

The SKCCC Biostatistics Shared Resource was established in 1986, is subject to external peer review as part of the SKCCC Cancer Center Support Grant, and continues to provide consultation and expertise regarding study design (including validity of the overall design, feasibility of meeting objectives, sample size and projection of study duration), recommendations concerning key infrastructure (data management and computer systems support), data analysis, preparation of reports and assistance with manuscript writing, and development of new biostatistical methods if required by the project.  Personnel associated with this Shared Resource include Drs. Steven Piantadosi (Resource Director), Steven Goodman, Giovanni Parmigiani, Elizabeth Garett-Mayer, Jeanne Kowalski, Elizabeth Sugar, Leslie Cope, Amy Berrington, Xiaobu Ye, Zhe Zhang, Marianna Zahurak, Amanda Blackforrd, Alla Guseynova, and Helen Cromwell.

The SKCCC Bioinformatics Shared Resource was established in a pilot phase using institutional funds in September of 2004, and was approved by peer review at the last SKCCC Cancer Center Support Grant competitive renewal. The Bioinformatics Shared Resource guarantees the availability of comprehensive bioinformatics expertise to all SKCCC members, including all Prostate Cancer SPORE Program investigators. The resource comprises faculty and support staff able to support data acquisition, statistical quality control, data analysis and development of innovative customized bioinformatics tools, and education. The resource stabilizes and expands existing high-quality expertise in the areas of computational molecular biology, bioinformatics, and computing-intensive statistical genetics.  Personnel in this Shared Resource include Drs. Giovanni Parmigiani (Resource Director), Steven Piantadosi, Leslie Cope, Elizabeth Garrett-Mayer, Alison Klein, Jeanne Kowalski, Sining Chen, Zhen Zhang, YiZhi Zhang, Alla Guseynova, Mike Fox, and Amanda Blackford.

L. Data and Research Resources Sharing Plan

All data and unique research resources developed by Johns Hopkins Prostate Cancer SPORE investigators will be made available to the public.  New model systems and reagents will be shared via scientific presentation and publication. The Prostate Cancer SPORE investigators affirm their willingness to collaborate and share data freely with the other Prostate Cancer SPOREs, to participate in inter-SPORE collaborative research studies, to plann and attend SPORE workshops and symposia, and to be able and willing to share data and research resources with each other and the NCI.

Data Security and Confidentiality: All research and patient-related information systems at Johns Hopkins comply with the Johns Hopkins General Security and Network Administration Standards, available at http://www.it.jhu.edu/divisions/jhmcis and covering General Network Administration Standards, Security Standards and Practices, and LAN Backup Standards. These standards are enforced and ensure a high level of security and confidentiality, consistent with HIPAA guidelines.  All databases to be assembled and/or used in pursuit of SPORE Program objectives comply with these rules.  The SKCCC Information Technology Shared Resource has experience in implementing integration architectures that achieve this goal within the guidelines of HIPAA and University Standards.  Data exported from these databases for analysis by SPORE Program investigators will be free of patient identifiers and stored on password-protected backed-up hard disks only. Backup copies are kept at separate locations.

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