The following are intended as a capsular summary of NIH's range of activities in prostate cancer research, elaborated on in this report:
NCI established the Cancer Genome Anatomy Project (CGAP). The goals of CGAP are to build an infrastructure of resources, information, and technologies. These will provide a platform for the establishment of an index of all genes that are expressed in tumors and support development of new technologies that will allow high throughput analysis of gene and protein expression as well as mutation detection. The tumor type with the highest representation in the CGAP effort is prostate cancer.
NCI established a Prostate Cancer Progress Review Group (PRG) that has reviewed NCI's 1997 prostate cancer research portfolio in the context of the emerging opportunities for research. The report of the Prostate Cancer PRG was issued in August 1998. The portfolio review identified approximately 500 NCI projects related to prostate cancer.
In 1997-1998, NCI funded (in total or in part) 246 clinical trials in prostate cancer including 80 Phase III studies (clinical trials involving new interventions closest to approval) and 37 Phase I trials (representing the newest potential therapeutic agents for prostate cancer). Thirteen NCI trials in prostate cancer are underway at the NIH Clinical Center.
NCI clinical studies in prostate cancer have significant African American participation. One NCI study shows that 14.7 percent of men enrolled onto NCI sponsored prostate cancer treatment trials are African American while 10.3 percent of the 179,300 Americans diagnosed with prostate cancer are African American.
NCI staff and the Department of Defense have collaborated in a study of treatment data and shown that equal treatment yields equal outcome within stage. This finding suggests that all NCI efforts to improve prevention, diagnosis and treatment of this disease benefit all patients equally. However, NCI staff analyzing Surveillance, Epidemiology and End Results (SEER) Program data have shown that there are tremendously different patterns of care among African American and White men with prostate cancer.
NCI's ongoing Prostate Cancer Prevention Trial (PCPT) involves 18,000 healthy men over the age of 55 to determine if the drug finasteride can prevent prostate cancer.
NCI's ongoing Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is assessing the efficacy of prostate cancer screening. New PLCO sites are being added to enhance minority patient accrual.
NCI is sponsoring two trials in which "watchful waiting" is being compared in terms of outcome with surgical removal of the prostate and with radiation therapy. These trials are intended to distinguish patients needing more aggressive treatment from those with slow growing tumors that will never threaten their lives.
NCI has established the Urologic Oncology Branch within the Division of Clinical Sciences. Major areas of emphasis of this branch are prostate and kidney cancer.
NCI has established a new fellowship program in urologic oncology that will have as a major focus the training of clinician-investigators to reduce the burden of prostate cancer in all segments of our society.
NCI has conducted a large interview-based study of prostate cancer in African Americans and Whites. Analysis of the results has not yet revealed any specific factor that could explain the racial differences in risk. However, further studies are underway, including an extensive evaluation of the role of different components of the diet.
NCI funded or co-funded 11 prostate cancer epidemiologic studies beginning in September 1995 with study durations of three to five years. Eight of the 11 studies include an assessment of risk factors among African American men.
An NCI Intramural Prostate Cancer Working Group has been formed, the goal of which is the investigation of genetic alterations underlying human prostate cancer development and progression. Emphasis is placed on the integration of basic research, clinical information, and developing technologies and methodologies.
NIDDK has strong programs in basic and clinical investigations on prostate disorders. The NIDDK supports an active portfolio of basic and clinical investigations on prostate disorders - benign prostatic hyperplasia (BPH), prostatitis, and research related to prostate cancer-including genetic and hormonal aspects of prostate growth regulation. Basic research includes studies of genes and factors - including hormones, enzymes, neural factors, and vitamins - that affect or may affect or regulate prostate growth or transformation to the malignant state; prostate cell structure and function in BPH; biomarkers of BPH; and prostate stem cells and stem cell genes.
NIEHS and NHGRI focus on identifying genetic changes in the cell which lead to initiation and progression of prostate cancer as well as the role of gene-environment interactions in prostate cancer development.
NCRR provides infrastructure for advancing clinical and basic studies throughout the nation.
NIA addresses the problem from its epidemiological characteristics as a disease of high prevalence in old age.
NINR supports important efforts in research on symptom management following prostate cancer surgery such as urinary incontinence and pain and also conducts research on nursing interventions to improve quality of life including sexual functions.
NIDCR seeks a more complete understanding of bombesin receptor function in cancer.
NIMH studies the effects of stress and emotion in men with prostate cancer.
The Cancer Genome Anatomy Project
The CGAP is an interdisciplinary program to establish information, reagents, and technological tools needed to decipher the molecular anatomy of a cancer cell. The overarching purpose of the CGAP is the comprehensive molecular characterization of normal precancerous and malignant cells. The Human Tumor Gene Index was initiated in May 1998 with the initial goal of identifying genes expressed during development of five major cancer sites - breast, colon, lung, ovary, and prostate. Over 80 cDNA libraries have been prepared and more than 300,000 partial cDNA sequences have been generated. To date, about 10,000 putative new genes have been discovered as a result of the CGAP. All CGAP data and reagents are made available to the research community without restriction via the CGAP website located at http://www. ncbi.nlm. nih.gov/ncicgap/.
To begin to examine gene expression profiles during human prostate cancer progression we prepared and sequenced clones from 20 cDNA libraries. We used a range of prostate-derived tissue sources, including microdissected cells (normal epithelium, prostatic intraepithelial neoplasia, invasive tumor, metastatic tumor), bulk tissue samples (normal, tumor), and matched normal and tumor prostate cell lines. A total of 40,637 sequence reads were performed which identified 7,677 unigene clusters expressed in normal or cancerous prostate tissues, 354 novel human genes, 146 prostate specific genes, 389 prostate unique genes, and 400 candidate differentially expressed genes. Comparison of cDNA library sequences derived from microdissected cells, cell lines, and bulk tumor libraries identified both an overlapping and distinct population of expressed genes from each group. Library normalization increased both the diversity of sequences and rate of novel gene discovery.
The Prostate Cancer Progress Review Group
The NCI has supported and continues to support a very wide range of basic, clinical, and population-based research projects to elucidate the causes and biology of prostate cancer and to develop strategies and technologies for preventing, detecting, diagnosing, and treating prostate cancer. New data suggest that the application of these research results may save lives, as evidenced by the declining mortality rate for prostate cancer among some populations. This ongoing research effort has provided a wealth of new scientific opportunities that if pursued may further advance our understanding of prostate cancer and our ability to care for men with this disease and those at risk of it. The NCI Director constituted the Prostate Cancer Progress Review Group (PRG) that began its work in April 1997. The Prostate PRG is one of two pilot groups that were established to help NCI sharpen the focus of its large, site-specific research programs. The other PRG focused on breast cancer. The PRGs are part of NCI's new overall planning framework, which also relies on Working Groups and Program Review Groups for evaluation, and planning of the research portfolio.
Specifically, the PRG was given six charges: 1) Identify and prioritize scientific needs and opportunities that are critical to hasten progress against prostate cancer. 2) Review an NCI-prepared portfolio analysis of the current research program. 3) Review recommendations from the research community generated through Prostate Cancer Roundtable meeting and Expert Panel reports. 4) Review recommendations from the prostate cancer advocacy community and from stakeholders. 5) Define and prioritize the research agenda. 6) Develop an action plan encompassing both operational and strategic components of the NCI's prostate cancer enterprise, using the current research program as the baseline for recommended actions.
Members of the PRG were selected from among prominent members of the scientific, medical, industrial, and advocacy communities to represent the full spectrum of expertise needed to develop comprehensive recommendations on NCI's prostate cancer research agenda. The membership was also selected for its ability to take a broad view in identifying and prioritizing scientific needs and opportunities that are critical to advancing the field of prostate cancer research. The full report of the Prostate Cancer Progress Review Group can be read on line at http://wwwosp.nci.nih.gov/Planning/PRG/default.htm A hard copy can be ordered by calling 1-800-422-6237, or by sending an e-mail message to nciosppcaprg-r@mail.nih.gov.
The Process of Reviewing the Prostate Cancer Portfolio
The PRG assessed the current NCI research portfolio in prostate cancer. The aim of the portfolio review was to describe the ongoing NCI prostate cancer research effort, which would then serve as a baseline for the PRG in formulating its recommendations. The NCI prostate cancer research portfolio was reviewed within the context of scientific questions and/or research areas. It became apparent during the Portfolio Analysis that if the NCI could develop a Common Scientific Outline that could be used for any specific cancer for comparing research between scientific organizations, this would be very beneficial to NCI and the cancer community at-large. The PRG, in addition to its main charge, played a critical role in providing a basis for the NCI to build this new and important tool, which will provide a standardized way to scientifically categorize NCI supported research. This scientific categorization will allow for thoughtful prioritization of research by identifying strengths, weaknesses, and trends within the NCI research portfolio. The Common Scientific Outline may be applied to each type of cancer individually (e.g., prostate, breast, lung, ovarian, etc.) to identify gaps in research, commonalities among cancer research fields that may be capitalized upon, or duplicative efforts that could be streamlined. A concrete example is the current collaboration between the NCI and the Department of Defense (DoD). The DoD is piloting the NCI Common Scientific Outline within the DoD's recent Prostate Cancer Research Program Announcement. The information from this pilot should provide the basis for future use of a Common Scientific Outline by both agencies. This could allow the NCI and DoD, for the first time ever, to compare effectively their individual research portfolios and to identify those areas that are undersupported or instances of duplication of effort between the two agencies.
Identification of Needs and Resources
The PRG used the portfolio analyses as a "baseline" in formulating their recommendations. Throughout their deliberations, the PRG relied extensively on input from outside experts. Key sources of information included:
PRG Roundtable. In June 1997, over 100 members of the prostate cancer communities, including academic and industrial scientists, clinicians, and advocates, met in Chantilly, Virginia for intensive discussion. PRG members nominated the participants. The Roundtable was an open forum designed to identify and formulate key scientific questions that should be addressed in the next five to 10 years in prostate cancer research.
Expert Panels. The PRG formed seven panels of between three and 20 experts in the fields of Clinical Trial Design and Implementation, Prognostic Marker Validation, Radiobiology, Screening and Early Detection, Gene Therapy and Vaccines, Gene Technology and Gene Identification, and Molecular Epidemiology. The Expert Panels examined in detail the opportunities, questions, issues, and resources that will enhance the field of prostate cancer research. The Expert Panels were encouraged to "be visionary" and to establish expectations of where the field could be, or should be, in five years and beyond. Panels met between December 1997 and January 1998.
Stakeholder Groups. To ensure that the professional and advocacy communities were fully represented, the PRG invited the input of 32 "stakeholder" groups - professional societies and advocacy groups with an interest in prostate cancer research. Letters were sent to representatives of the groups encouraging participation, and a special web site was set up to collect feedback.
Overall Results of the PRG Analysis of the NCI Portfolio in Prostate Cancer
After reviewing the portfolio of grants funded by NCI, the PRG estimated that there was over $82 million in 1997 supporting research in prostate cancer. While the process of attribution of many scientific projects was difficult - funded research projects often address diverse research topics as well as cancers in multiple tissues - the PRG was able to identify the major focus of projects and sorted them according to the major research areas. It is important to note that some projects overlap topic areas and are found in two or more categories. Epitomizing the issue of overlap are animal models for prostate cancer. Reliable and robust animal models for prostate cancer are recognized by all concerned as being of critical importance, and so the PRG dealt with this as a separate category. However, the models are being used to study biology, detection, diagnosis, prevention, and therapy, thus making it difficult to code a given project in only one category.
Projects related to prostate cancer conducted within the NCI Intramural Research Program as well as those sponsored by the Extramural Research Program were included in the portfolio review conducted by the Prostate Cancer PRG. In the sections that follow, an attempt is made to convey the breadth of the NCI portfolio in prostate cancer research.
Portfolio in Biology and Epidemiology
Understanding the molecular genetic changes associated with progression from pre-malignant to malignant states is essential to interrupt the process. The overall emphasis in research supported in this area is to understand how hormonal, extracellular matrix and possibly infectious factors modulate the expression of specific genes and, more importantly, the functional significance of these genetic changes. Investigations include: the delineation of genetic events in the development of prostate cancer; the role of sex hormones, various growth factors, their receptors and binding proteins in the malignant transformation; and the role of cell-cell and cell-matrix interactions in prostatic carcinogenesis
One of the major challenges in understanding the pathogenesis of prostate cancer continues to be the development of relevant models that mimic changes that occur in human prostatic neoplasms. Currently available models to study prostatic carcinogenesis include carcinogen-induced or transgenic animal models, normal prostatic epithelial cells exposed to various transforming agents in vitro, and use of human prostatic tissues (normal, benign and malignant).
A high proportion of indolent lesions characterizes prostatic neoplasms while only a small percentage of these lesions become invasive. Since it is not possible to predict the biological potential of these lesions based on histology alone, molecular mechanisms that distinguish non-invasive from aggressive lesions is a research area of high priority. Hormones and other signal transducers contribute to the complex cascade of the metastatic process including cell adhesion and motility, matrix degradation and angiogenesis.
Classical epidemiologic studies have identified heritability, i.e., familial clustering, positive family history, and Mendelian inheritance patterns, as one of the determinants of prostate cancer. In extending these findings while the search for predisposing gene(s) continues, currently supported investigations are pursuing several research directions. Future challenges will include elucidating the effects of environmental modulation of gene expression and gene-environment interactions and assessing risk of combined factors, such as a heritable component, intrinsic host and behavioral patterns, and environmental exposures.
Earlier studies have considered various environmental, biological, and lifestyle factors with conflicting results, often due to methodological issues. As molecular technology provides the capability for precision and increased power in epidemiologic studies, research will be needed to address relevance, validity, and applicability of molecular determinations in populations. Utilizable biological specimen banks will be invaluable. Most limiting and complex are the unanswered questions regarding the identification of influential environmental exposures.
Portfolio in Preventing Prostate Cancer
There is a 100-fold variation in prostate cancer incidence worldwide. The factors involved in this extreme variation of prostate cancer incidence must be investigated and identified to allow development of rational prostate cancer prevention strategies. Although research on hormonal factors of prostate cancer is the currently favored model, research on other modulable exposures, for example selenium intake, will require further investigation.
Chemoprevention of prostate cancer development is an important research area given the likelihood that modulable exposure (dietary factors, carcinogens etc.) may explain the 100-fold variation in prostate cancer incidence observed worldwide. There will continue to be a substantial need for developing cellular models for screening of agents and, in addition, reliable animal models for testing new agents before use in human subject clinical trials.
Portfolio in Detection and Diagnosis of Prostate Cancer
The effect of screening on prostate cancer mortality statistics is unknown. The primary method of screening for prostate cancer, at present, is by serum analysis for prostate-specific antigen (PSA). Elevation of PSA may indicate prostate cancer; however, several other common benign conditions, including Benign Prostatic Hyperplasia (BPH), are known to be associated with an elevated PSA. The widespread measurement of Prostate Specific Antigen (PSA) levels in blood has led to an increased detection rate for prostate cancer. Approximately 30 percent of early stage disease will progress to clinically relevant disease within the lifetime of the patient. Thus, there is a critical need to be able to identify those patients at risk of progression who would benefit from aggressive therapy while sparing low-risk patients the morbidity resulting from aggressive treatment of indolent disease.
The metastatic potential of prostate tumors is determined by the capacity of the tumor cells to escape the environment of the prostate gland, to survive distribution throughout the body, to implant at a distant site and to stimulate the new environment to produce the necessary vascularization and metabolic conditions to facilitate cellular proliferation. Identifying molecular alterations in tumor cells that reflect the tumor cells acquisition of any of these biological capacities would identify those patients at highest risk of metastatic disease.
Many prostate cancer patients initially respond to hormone therapy, only to fail with the appearance of recurrent disease that is no longer responsive to androgen or androgen analogs. The biological basis for androgen insensitivity is not well understood; significant efforts are being made to determine the role of the androgen receptor in the disease process. Extremely sensitive molecular technologies detect prostate specific mRNAs, such as PSA mRNA, in the blood and bone marrow in a subset of patients with organ confined disease. Initial studies have shown that patients with extraprostatic cells following surgery or radiation therapy are at high risk of treatment failure. Continuing studies are attempting to identify markers specifically associated with prostate cancer cells that will improve the specificity of the assay.
Prostate cancer is a heterogeneous disease with apparently independent foci of cancer scattered throughout the gland. The cancer foci have different malignant potentials and do not pose equal risks for the patient. Heterogeneity confounds the interpretation of prostate biopsies since it is not possible to be certain that the most clinically relevant foci of cancer have been detected.
Families have been identified in which the number of family members afflicted with prostate cancer is significantly higher than might be expected based on the rate of disease in the entire population. These families are particularly characterized by the early age of disease onset.
The incidence and severity of prostate cancer varies in different ethnic populations. African American men are more than twice as likely to die of prostate cancer than Caucasian men. In African American men, prostate cancer is also generally more advanced at the time of diagnosis. The biological basis for this racial difference in prostate cancer is not understood.
There are a number of high-priority research and development areas for imaging modalities in the detection and diagnosis of prostate cancer. Ultrasound technology continues to be an important tool in the detection of prostate cancer. Another focus of prostate imaging research is the use of magnetic resonance imaging and spectroscopy that have advanced technologically to the point where large-scale clinical trials could be initiated for the prostate.
Portfolio in Treating Prostate Cancer
Clinical management of prostate cancer has, until recently, been restricted by a limited armamentarium of classical modalities - surgery, radiation, androgen deprivation, and (minimally active) cytotoxic chemotherapy. There remains a need for a broad program for testing novel approaches, compounds, and targets, for prioritizing these, and for answering the practical questions necessary for preparing these for clinical testing.
Management of prostate cancer presents some unique complexities for oncologists and other clinicians. One set of difficulties is the inability to reliably distinguish in advance those tumors whose behavior will be aggressive from the larger subset of indolent tumors, the very long intervals before clinical trials become mature, and the fact that good surrogate endpoints are not yet known. The entire clinical trials capacity for prostate cancer needs to be expanded since the participation of large numbers of patients can reduce somewhat the time to definitive analysis of these clinical trials. Moreover, only about 30 percent of patients diagnosed with limited stage prostate cancer will eventually progress to have clinically relevant disease. This complicates profoundly the evaluation of therapies because the majority of patients whose clinical course is inherently benign can overwhelm recognition of treatment effects in the minority.
Progress in clinical therapy of other malignancies has generally accompanied our capacity to refine both risk classification and prediction of therapeutic response or non-response. This has made it possible to test treatments in more homogeneous clinical cohorts, with the result that ineffective therapy can be abandoned in favor of earlier testing of novel approaches. The exploration of defects in cellular regulatory, signaling, and apoptosis pathways in prostate cancer as determinants of hormonal resistance is likely to provide a productive field for testing in the clinical arena in the near future.
Clinical intervention trials, both therapeutic and chemopreventive, have been hampered by the insensitivity of clinical evaluations for prostate cancer, the unwillingness of patients and clinicians to undertake repeated uncomfortable invasive procedures, and the lack of reliable non-invasive methodologies for response assessment. This is an area in which the research portfolio is currently virtually empty. Imaging technologies per se, however, make up an extremely active field of research and development, with the potential to dramatically improve our evaluation of potential chemopreventative approaches and of local therapies such as various modalities of radiation, cryosurgery, etc. and of the role of adjunctive hormonal, anti-invasive, or other therapy.
Portfolio in Prostate Cancer Survivorship and Morbidity
The Prostate Cancer Outcomes Study (PCOS) is a major NCI study being conducted by six out of the 10 registry organizations that participate in the NCI's Surveillance, Epidemiology and End Results (SEER) Program. The objective of PCOS is to evaluate recent diagnostic and treatment practice patterns among men diagnosed with prostate cancer in order to evaluate the prevalence of long-term urinary, bowel, and sexual function complications subsequent to initial treatment. It is recognized that more needs to be done in managing incontinence and sexual dysfunction.
Prostate cancer, as the most commonly diagnosed cancer among men in the U.S., exerts an enormous impact on patients. In addition to the expense of an estimated $5 billion spent annually in direct medical care costs there are questions about quality of life. The NCI portfolio includes support for the development of instruments to assess quality of life and interventions to increase health-related quality of life of prostate cancer patients. Symptom management specific to the sequelae of prostate cancer therapy should be examined more broadly.
Portfolio in Prostate Cancer Surveillance
Diet is monitored among the general population, using nationally representative samples, and among special populations defined by gender, age, race, and ethnicity. Selected research priorities include monitoring trends in intakes of specific food groups and nutrients; identifying food sources of nutrients; and assessing demographic and other factors that affect changes in dietary behaviors over time.
NCI monitors the dissemination of state-of-the-art diagnostic and treatment modalities. This research is being conducted using survey data, tumor registry information from the Surveillance, Epidemiology, and End Results (SEER) Program, and from administrative data sources such as Medicare claims linked with SEER data. Innovative approaches are being developed to relate current and future trends in PSA usage to prostate cancer incidence and mortality. Other innovative methodologic approaches that are being used to model trends in prostate cancer include incidence-based mortality and change point techniques.
Portfolio in Scientific and Public Resources
The National Cancer Act of 1971 explicitly instructed the Director of the NCI regarding communication, and the NCI sees communication as a critical component of the NCI's mission. The NCI not only engages in education and communication but also supports research into how to educate and communicate effectively. Many of these efforts are crosscutting, but some relate to specific cancer sites.
Cancer center support grants (CCSG) provide support to the peer-reviewed research base of a cancer center within the parent institution. In addition, development grants (R21) for new research programs in prostate cancer are exploratory-developmental grants to promote the development of institution-wide multidisciplinary research programs in prostate cancer.
Specialized Programs of Research Excellence (SPOREs) focus on translational research, i.e., the bi-directional exchange between basic and clinical science in order to move basic research findings from the laboratory to applied settings involving patients and populations. The ultimate goal of the SPORE program is to bring novel ideas that have the potential to reduce cancer incidence and mortality, improve survival, and to improve the quality of life to clinical care settings. At present, there are three Prostate Cancer SPOREs: at the Baylor College of Medicine, at the Johns Hopkins Cancer Center, and at the University of Michigan Cancer Center. Among the prostate cancer research resources supported through the NCI are the Community Clinical Oncology Program (CCOP). These are organizations comprising one or more facilities (e.g., community hospitals, clinics, doctors' offices) which together function as an infrastructure for the implementation of clinical trials in the community.
Human tissue resources include the Cooperative Human Tissue Network, a tissue procurement network that provides tissues on request to investigators. Approximately 10 percent of the tissues provided through this network are prostate. This effort is spread over the four sites: Case Western University, Ohio State University, the University of Alabama, and the University of Pennsylvania. The Developmental Therapeutics Program (DTP) uses contract resources to discover, test and develop anti-cancer agents. DTP's developmental resources provide for chemical synthesis, formulation, pharmacology, and toxicology testing for promising agents through the NCI's Decision Network Committee.
Recommendations of the PRG
While the dollar amount and number of grants attests to a substantial commitment of NCI to research in prostate cancer, the PRG nonetheless identified gaps in the research agenda and major new opportunities that could move the pace of research in prostate cancer forward over the coming decade. The PRG examined the research portfolio and developed a ranked listing of priorities for research and the resources needed to support an expanded program of research. Their recommendations can be summarized as follows:
Prostate Cancer Biology, Progression, and Metastasis: To improve diagnosis, prevention, and treatment of prostate cancer, it is crucial to focus future research on molecular, cellular, physiological, and pathological events that lead to uncontrolled cell growth and metastasis. In addition, it is critical that we define the biochemical and molecular events that govern the continuation of prostate development from early embryogenesis to the onset of adulthood, through maturation, aging, and death.
Etiology and Primary Prevention: To gain a better understanding of the genes that are important in the development of prostate cancer, NCI should support an infrastructure that will aid studies of families with apparently hereditary prostate cancer. NCI should also support studies of environmental and behavioral factors, such as diet and exercise. Finally, NCI should support research and development of new technologies to identify risk factors and how environmental factors modify predisposing risks.
Early Detection, Diagnosis, and Prognosis: Progress in this area will depend on the development and refinement of tests to detect prostate cancer to ensure that, whenever possible, the tests detect only those cancers with the potential to kill their host if left untreated. NCI should also place major emphasis on the development, validation, and application of biologic markers or determinants that can provide reliable prognostic information. At the same time, NCI should continue to support clinical trials to determine whether screening for prostate cancer reduces the risk of dying from this disease and should substantially expand studies of the effects of early detection on morbidity and quality of life.
Laboratory and Clinical Models: A constellation of models must be developed to mimic distinct characteristics of human prostate cancer. These models then must be validated to permit a predictable level of extrapolation to humans. Additional prostate cancer cell lines must also be developed.
Staging and Treatment of Localized Prostate Cancer: New techniques to detect metastatic cells, predict the response of individual cancers to different forms and intensities of therapy, and diminish treatment-related side effects are needed. In addition, the Review Group noted that prostate cancer appears to be a particularly promising candidate for gene therapy and recommended significant research in this area.
Systemic Therapy: Systemic therapies are needed for tumors that can no longer be cured by local treatments, such as surgery or radiation therapy, alone. The PRG noted that the design and execution of clinical trials of systemic therapies for prostate cancer is critically important, and called for substantial and sustained investment in the infrastructure needed to support clinical trials, develop clear endpoints, and follow up treatment outcomes.
Outcomes Research: "Outcomes" include disease-specific and patient-focused endpoints used to describe the results of various interventions in the management of prostate cancer. Better instruments are needed to assess more accurately the impact of both the treatment and the disease on patient-focused outcomes. In addition, more data are needed about all aspects of prostate cancer patients' and survivors' quality of life.
Resources Needed: The PRG unanimously agreed that the education and training of investigators who will pursue research in prostate cancer should receive top priority. Other resource needs include databases and bioinformatics to ensure that the vast amount of information being generated can be assimilated and exploited; the establishment of a National Prostate Cancer Repository to procure and distribute tissue samples from prostate cancer patients; the development and dissemination of new animal models and cell lines; the development and dissemination of new technologies for research in prostate cancer prevention, diagnosis, and treatment; and increased activity in the area of clinical trials design, including the development of a special prostate cancer trials consortium.
New Initiatives in Prostate Cancer Research
Partially in response to the report of the Prostate Cancer PRG and also as a part of its normal planning process, the NCI has begun a number of new initiatives with relevance to research in prostate cancer. NCI is also seeking to communicate more effectively both new and long-standing initiatives to the extramural research community to stimulate their increased involvement in the battle against prostate cancer. Toward that end, NCI has recently added to its website a page describing initiatives applicable to prostate cancer research these initiatives. The page can be accessed at http://www.nci.nih.gov/prostate.html. It contains descriptions of initiatives, hotlinks to other relevant sites, and NCI contact information. The topics covered in this webpage are:
Funding Grants as Exceptions to the Payline. Three times a year the NCI funds, as "exceptions" to its grant policies, a certain number of grants whose priority scores fall below the payline established as the cutoff for that year. This is one particularly important way of supporting meritorious proposals in particular areas. We plan to do this selectively for meritorious proposals in prostate cancer, particularly those that deal with topic areas that the Prostate PRG considered especially compelling or important gaps in NCI's prostate cancer portfolio.
The Cancer Genome Anatomy Project. NCI established the Cancer Genome Anatomy Project (CGAP) to build an infrastructure of resources, information, and technologies that will provide a platform for the establishment of an index of all genes that are expressed in tumors. CGAP will also support development of new technologies that will allow high throughput analysis of gene and protein expression as well as mutation detection. The tumor type with the highest representation in the CGAP effort is prostate cancer. NCI is particularly interested in engaging members of the research community with access to specimens representing the different stages/grades of prostate cancer with the aim of understanding genes relevant to prostate cancer progression and metastasis. A focus of this effort will be enhancing our understanding of the relationship between prostate and bone (to which prostate cancer frequently metastasizes).
Director's Challenge for Molecular Diagnostics. This initiative challenges the scientific community to develop a tumor classification system that is based firmly on the cell biology of cancers, rather than on microscopic appearance. The assumption behind this initiative is that a biologically based classification scheme will be vastly more informative than a morphological one and will lead directly to better ways of predicting the behavior of cancers and selecting effective therapy for patients. Prostate cancer is a particularly important area of application for this initiative, because its behavior is so variable from patient to patient. Many prostate cancers remain confined to the gland itself, even after years of observations, while others spread rapidly to distant organs. Current morphological classification schemes capture only a small portion of this variability and suggest little about optimal ways to select therapy.
Early Detection Research Network. This Network addresses the crucial problem of how to develop clinical useful blood tests to detect cancers early, before they have had a chance to spread beyond the point at which cure is assured. The goals of the network will be to discover and coordinate the preclinical development, evaluation, and application of biomarkers/reagents for the earlier detection of cancer and risk assessment. We imagine the output of this Network to be a series of tests for various cancers that can be used effectively to screen for cancer in large populations or in populations at particular risk. Prostate cancer will be a particularly important focus of activity within the new network, and we anticipate that the PSA test is a harbinger of better things to come.
Cancer Genetics Network. For prostate cancer, as for other tumor types, the genes a person carries is one determinant of his chances of getting the disease. The identification of susceptibility genes for prostate cancer is currently at the very early stages. The Network will serve as a platform for studies of genetic susceptibility to cancer and for the education of patients and their families. Incorporating all necessary measures for assuring confidentiality, it will, for example, include a registry of families with multiple cases of cancer. The Network will serve as an educational resource to provide counseling to members of such families and will provide information about studies in early diagnosis and prevention that they might be interested in joining. The Network will also provide a means of enabling discovery of the set of genes responsible for prostate cancer susceptibility.
International Consortium on Prostate Cancer Genetics (ICPCG). This consortium of over 25 groups and multiple investigators performs collaborative studies on the epidemiology of prostate cancer and, in particular, on the discovery and characterization of prostate cancer susceptibility genes.
Diagnostic Imaging. Assessing a tumor's location accurately is clearly crucial to the planning of curative therapy, whether surgery or radiation. The recently funded imaging network will function as a national consortium for the evaluation of new imaging technologies applicable to all body sites. Prostate cancer will be a core component of their agenda. NCI expects also to announce later this year an initiative supporting the development of image-guided minimally invasive treatment for prostate cancer. The goal will be to develop techniques that will accurately define the anatomic extent of localized prostate cancer and to concentrate tumor killing modalities (radiation, heat, cold) within the involved area in a way that spares normal tissue, preserves function, maximizes quality of life, and reduces cost of care. We also anticipate that the further development of "molecular imaging" - the ability to display the molecular pathways and intracellular functions that determines how a tumor behaves - will have important applications to prostate cancer treatment. NCI will soon establish a number of centers for molecular and functional imaging, whose work will concentrate on these goals.
Clinical Trials Restructuring. NCI is currently re-engineering its national clinical trials program, to make it faster, more flexible, more easily accessible to patients, and more responsive to the key questions in therapy that need to be asked and answered quickly. Tumors of the lung and the genitourinary system, including prostate, will be a particular focus of the implementation effort. A number of features of this massive effort are particularly noteworthy:
During the next year we will begin a series of "State of the Science" meetings to define the key areas for emphasis in prostate cancer research.
We will implement a new competitive grant program intended to support investigators with novel ideas for prostate cancer treatment. This program will feature a streamlined applications procedure and rapid review.
We will convene a meeting of experts in prostate cancer and clinical trial methods to coordinate development of a common methodology for the conduct and analysis of prostate cancer trials, including common endpoints.
We will convene an expert group to develop a consensus around the important clinical question of how best to manage the patient with a rising PSA after surgery or radiation therapy of the primary tumor.
Informatics and Clinical Trials. In close coordination with the overall clinical trials restructuring efforts, we are coordinating the development of an up-to-date national infrastructure for clinical research. The obvious need here is to enable the linkage, transfer, and analysis of biomedical information relating to cancer. The initial emphasis is on systems to support clinical trials. NCI is currently collaborating with parallel efforts supported by CapCure targeted specifically to needs in prostate cancer. We also expect significant collaborations with interested elements in the computer industry.
Tissue Banks. Successful development of molecular diagnostics depends on availability of tumor tissue specimens. NCI will shortly announce an initiative to create a National Prostate Cancer Tissue Resource, similar to its already successful Cooperative Breast Cancer Tissue Resource.
Correlative Studies Using Specimens from Treatment Trials. Establishing correlations between the molecular characteristics of tumors and the results of treating patients is a direct way of applying new knowledge about tumor biology to the clinic in an effort to benefit patients. NCI has invited investigators to submit proposals that correlate laboratory findings from tumor tissue stored in the tissue banks of its clinical cooperative groups with the actual results of therapeutic studies performed by the cooperative groups. Once such correlations are established by studies like these, the results can be used in the general care of patients to provide much more accurate information about likely outcome and optimal choice of treatment.
Animal Models. A very high NCI priority is the development of animal models that truly reflect the behavior of human cancer and its responsiveness to therapeutic and preventive maneuvers. Such models would have a profound effect on our ability to test new drugs and new approaches to treatment. Prostate cancer investigators have already had some success developing more relevant models. To extend this success, NCI will establish a consortium that will develop and validate models for human cancer. We will assure that prostate cancer model development will take advantage of this initiative. In particular, models for progression and metastasis to bone are of high priority.
Clinical Trials in Prevention and Early Detection. The rationale for early detection and prevention of prostate cancer is obvious and needs no further elaboration here. We expect during the next year to fund a number of clinical trials in prostate cancer prevention. It is likely that these trials will test the efficacy of dietary constituents, singly and in various combinations. We will also fund other trials assessing biomarkers of risk and early detection.
Rapid Access to Intervention Development (RAID). Investigators in academia and in small businesses may be faced with the prospect of having no means of getting compounds with promise for treatment into clinical testing. They may, for example, lack access to the resources necessary for preclinical development (scale-up chemical synthesis, formulation, pharmacology, and toxicology), that is necessary before clinical trials can be started. The RAID program places NCI's development resources at the services of academia and small business, on a competitive basis, so that no promising compound is barred from early testing in the clinic merely for lack of development resources. We expect that the RAID program will dovetail with the new pilot clinical grant program for prostate cancer described under item 8 above.
Rapid Access to Prevention Intervention Development (RAPID). This program will do for the prevention area in prostate cancer research what RAID does for treatment.
Health Services & Economics Research in Prostate Cancer. The NCI supports studies within its Cancer Surveillance Research Program (CSRP) on patterns of care and outcomes of prostate - cancer screening and treatment, including assessments of the quality of life. CSRP has conducted studies to describe the relationship between diagnostic testing patterns and prostate cancer incidence. It also supports the development of statistical and simulation models that help explain trends in incidence and mortality and evaluate the cost and effectiveness of cancer control interventions. Studies using administrative claims such as the linked data between Medicare and SEER are also supported.
Genetic Epidemiology Studies. The interaction between the genes we carry and the environment we live in is a subject of great current interest in cancer research. It seems likely that the great majority of cancer incidence will eventually be explained by interactions between genes and exposures. The NCI has recently issued Requests for Applications (RFA) and Program Announcements PA) in several areas that support prostate cancer research. Molecular Epidemiology of Prostate Carcinogenesis (PA) emphasizes interdisciplinary collaborations between laboratory scientists in molecular genetics and biology and cancer epidemiologists to develop and validate biomarkers for assessment of risk in population subgroups (for example, racial or ethnic groups), evaluate gene-environment interactions, and develop resources such as cohorts and repositories. The RFA on Interdisciplinary Studies in the Genetic Epidemiology of Cancer, offered jointly with the National Institute on Aging, seeks investigations to identify and evaluate the interactions of genetic and environmental risk factors leading to enhanced cancer susceptibility in individuals, families, and populations. This RFA also seeks research on factors influencing the increase in susceptibility with age, a key feature of prostate cancer incidence and mortality. Diet, Lifestyle, and Cancer in U.S. Special Populations (PA) focuses attention on the causes of cancer in population groups that experience unusually high cancer incidence and mortality, such as the experience of African Americans with prostate cancer.
Diet Nutrition, and Prostate Cancer. Several associations of dietary patterns with prostate cancer have been reported, but the evidence needs much more interdisciplinary research and analysis. Diets high in vegetables have been reported to decrease risk, and high fat, saturated fat, and animal fat to increase risk. Several micronutrients may affect prostate cancer occurrence, and the effect of food constituents on molecular events in the prostate is unknown. There is a 100 fold variation in prostate cancer incidence worldwide. NCI has been studying international incidence of prostate cancer for a number of years and is particularly interested in research projects related to understanding modulable factors (e.g., diet) in international variations in different racial and ethnic groups.
Surveillance. NCI plans a number of enhancements to its Cancer Surveillance Research Program. This program includes the Surveillance, Epidemiology, and End Results (SEER) database, which tracks trends in the incidence and impact of cancer in an approximately 14 percent sample of the US population. The enhancements will largely take the form of targeted special studies permitting the development of hypotheses concerning the origins of observed trends in incidence and mortality within the population. Prostate cancer is a particularly important area for emphasis, since the mortality from prostate cancer differs greatly according to ethnic group and we have little understanding of the basis for this variation. Similarly, the impact of screening on incidence, stage at diagnosis, survival, and mortality is an area of great current interest.
Leadership Initiatives. This outreach initiative is directed to special populations. It is intended to establish and maintain a structure for dissemination of cancer awareness and educational activities in minority and underserved communities. An additional goal is to build a community infrastructure to support participation in NCI-funded research. These programs will help convey information concerning prostate cancer and encourage participation of special populations in the clinical trials to answer many of the important questions in this disease.
Clinical Trials in Prostate Cancer
In 1997 and 1998, NCI funded (in total or in part) 246 clinical trials in prostate cancer including 80 Phase III studies (clinical trials involving new interventions closest to approval) and 37 Phase I trials (representing the newest potential therapeutic agents for prostate cancer). At the NIH Clinical Center 13 NCI trials in prostate cancer are underway. NCI clinical studies in prostate cancer have significant African American participation. In one NCI study 14.7 percent of men enrolled onto NCI sponsored prostate cancer treatment trials are African American while 10.3 percent of Americans diagnosed with prostate cancer are African American.
NCI's ongoing Prostate Cancer Prevention Trial (PCPT) involves 18,000 healthy men over the age of 55 to determine if the drug finasteride can prevent prostate cancer. NCI's ongoing Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is assessing the efficacy of prostate cancer screening. NCI is sponsoring two trials in which "watchful waiting" is being compared in terms of outcome with surgical removal of the prostate and with radiation therapy. NCI has conducted a large interview-based study of prostate cancer in African Americans and Whites. NCI funded or co-funded 11 prostate cancer epidemiologic studies beginning in September 1995 with study durations of 3-5 years. Eight of the 11 studies include an assessment of risk factors among African American men.
Prostate cancer incidence is higher among African Americans (1987-1991; 163 per 100,000) than Whites (121 per 100,000). The disease generally occurs more frequently among Whites in the United States than in Europe. Asians, in comparison, have very low rates of occurrence (for China, less than one percent of the rate among African Americans). In the United States, mortality due to prostate cancer is two-fold greater among African Americans (52 per 100,000) than Whites (24 per 100,000) (Cancer Rates and Risks, 1996). NCI investigations are ongoing to identify risk factors for prostate cancer in several populations, including studies of African Americans and Whites in the United States and of Chinese in Shanghai.
The Human Genome Project has undertaken an effort to identify genes associated with the familial transmission of risk. The NCI plans studies to evaluate genetic determinants of susceptibility in the general population, including the impact of metabolic (e.g., polymorphism for 5-alpha reductase) and functional polymorphism (e.g., polymorphism in the androgen receptor). These studies will take advantage of the natural variation in polymorphism frequency between African American, White, and Asian populations. Vasectomy has been linked to prostate cancer among U.S. Whites, but several other studies provided inconsistent results. This remains an area of continued investigation. An etiologic link with benign prostatic conditions is also being investigated. Dietary fat has been linked to prostate cancer in several studies. This and other dietary factors (e.g., level of consumption of fruits and vegetables) are now being examined as risk factors in the African American, White, and Chinese study groups, providing an opportunity to assess risk over a broad range of dietary patterns.
The Cancer Therapy Evaluation Program (CTEP) is the program within the Division of Cancer Treatment and Diagnosis (DCTD) of the NCI. This program plans, assesses, and coordinates all aspects of clinical trials including extramural clinical research programs, internal resources, treatment methods and effectiveness, and compilation and exchange of data as it pertains to the development and evaluation of anticancer agents. Many of the compounds in early development or preclinical development will be suitable for studies in prostate cancer, since broad phase II solicitations typically include the common solid tumors, including prostate cancer.
Some agents specifically being developed for patients with prostate cancer include:
Vaccine trials for patients with recurrent disease and for patients in an adjuvant setting, including vaccinia and fowlpox based vaccines. PSA-3 peptide vaccine and rF-PSA, the recombinant fowlpox PSA vaccine, are both scheduled for IND filing in 1999.
Combinations of estramustine with tubulin interactive agents (taxanes, CI-980, TCA, dolastatin 10)
A phase II trial has just been proposed to combine taxotere with follow-up treatment with thalidomide
Other relevant interesting biologic agents are in development. Trials of herceptin are being reviewed currently. Growth factor antibodies (anti-VEGF, anti-EGFR), and Newcastle disease virus for intratumoral injection should have prostate clinical trials this year.
Compounds with novel targets including arsenic trioxide, farnesyl transferase inhibitors (from several sources), rebeccamycin, epothilones (active in taxane resistant lines), rapamycine analyogue, PS 341 proteosome inhibitor, halichrondrin, and benzoylphenylurea are all potentially applicable to prostate cancer in 1999. Fenretinide will begin Phase II trials in prostate cancer shortly, to explore its anti-apoptoic mechanism, and other retinoids are being considered for clinical evaluation.
Other agents that target angiogenesis and the metastatic phenotype including vitaxin, endostatin, Sugen 5416 which inhibits VEGF signaling through Flk-1, and thalidomide as well as newer generation matrix metalloproteinase inhibitors will be used in trials in prostate cancer and a number of new clinical trials will begin in 1999. Patients with hormone sensitive disease will be eligible for a planned trial of leuprokide to maximal PSA reduction and then maintenance thalidomide, with reinstitution of leuprolide when PSA rises, plus thalidomide if not previously received.
Pharmaceutical collaborators will be sponsoring prostate cancer studies with a number of agents that are being co-developed with NCI, including: antisense BCL-2 and Onyx 015, E1B deleted adenovirus.
Among the more interesting of the new approaches being studied in CTEP-sponsored trials in 1997 and 1998 are: vaccine trials involving fowlpox or vaccinia viruses that express PSA, thalidomide (as an anti-angiogenic agent) + combined androgen blockade, and a number of agents that may target critical signaling pathways, bryostatin-1, phenylbutyrate + all-trans-retinoic acid, flavopiridol, perillyl alcohol, and dolastatin -10.
CTEP anticipates initiating Phase I or II clinical trials with approximately 25 new agents or combinations in the next 12 to 18 months. In addition, 15 clinical trials in prostate cancer are in review and should be active shortly, including six Phase I, five Phase II, three-Phase III and one correlative science study. Overall, 40 to 50 clinical trials are likely.
Clinical Trials Restructuring and Genitourinary Cancers
The NCI is engaged in a major restructuring of its entire extramural large scale clinical trials program, its mechanism for carrying out the research with the greatest immediate effect on patient care. This restructuring, the most far reaching such reorganization in 15 to 20 years, is one outcome of extensive analysis and review of NCI programs by extramural scientists, patients, and advocates carried out over the last several years at the request of the NCI Director. NCI proposes to jump-start an expansion of clinically related research on urologic cancers by making these malignancies the focus of the set of pilot projects that together constitute a new framework for promoting and developing a rationale and innovative clinical research program for any and all types of cancer. A permanent ongoing series of nationally constituted State of the Science meetings in genitourinary cancers intended to identify needed resources (such as standardized outcomes endpoints), gaps in clinical research portfolios, and new clinical research opportunities. The recommendations and work products of these State of the Science meetings will be disseminated broadly to active investigators, specialty societies, advocacy organizations, and to the public via NCI information resources. It is anticipated that broad availability of this information will serve to stimulate innovative proposals for clinical trials in genitourinary malignancies, especially where important opportunities are identified.
1999 will see the establishment of a new entity that will accept developed clinical phase III trial proposals from any source and select all those that are considered of high merit to utilize the funding and resources of the NCI's clinical program and network. This Genitourinary Cancer Concept Review Committee will be nationally representative and composed of oncologists and Genitourinary physicians, clinical and laboratory scientists with special expertise related to genitourinary cancer, patients and patient advocates, biostatisticians, and some NCI staff. This committee will review, critique, and rank all proposals for randomized trials. The highest-ranked trials will be opened in the national network of qualified clinical investigators and physicians, and their patients, and will receive NCI funding for the scientific leadership and for reimbursement for research personnel costs on a per-case basis.
Another key aspect of the new framework (and a distinct departure from prior practice) will be the creation of a system that will provide all qualified investigators and eligible patients, regardless of their institutional or other affiliation, access to enrollment on any NCI supported phase III clinical trial in genitourinary cancers. Another new entity, a Cancer Trials Support Unit (CTSU) will be created to facilitate the transition from the old system to the new system and to provide a way to verify the accuracy of data arriving from doctors not affiliated with the study leadership, and for reimbursing the costs associated with recruitment of patients.
We anticipate that, taken as a package, this would be a much more comprehensive approach than the more conventional approach of increasing the number of centers of excellence, or adding consortia or Cooperative Groups. By opening up the clinical trials system to investigators and patients, these new initiatives should serve to expand substantially the pool of new approaches and clinical trials in prostate and genitourinary cancer, as well as providing the means to promote and make accessible to all patients the studies of the highest priority questions.