National Institute of Diabetes and Digestive & Kidney Diseases
The NIDDK is firmly committed to play an important role in a broad NIH approach to the problem of prostate cancer. Particular research strengths of this Institute are in the basic biology of the prostate, the mechanisms of androgen action, clinical studies of benign disease of the prostate, and epidemiology of urologic disorders. These strengths provide a compelling base for major expansion, and position us to attack critical questions as part of a broad NIH approach to this major health problem. Our efforts are intended to integrate with and to complement the NCI plans. We will work to ensure continued integration of our programs with those of the NCI and other NIH institutes with active programs in this area. One important forum for coordination is the Urology Subcommittee of the Kidney and Urology and Hematology Interagency Coordinating Committee, chaired by the NIDDK.
Program Planning Process
Our planning process for development of prostate cancer programs has been undertaken with advice from the NIDDK Advisory Council. In March 1998, we convened an International Symposium on Prostate Growth, which resulted in the identification of a number of priorities for new research directions. To ensure continued external advice the Institute has convened a special Ad Hoc Prostate Planning Group to provide overview of existing programs and ongoing input into the development of new programs. The Institute leadership meets regularly with members of the urology community, particularly the leadership of the American Urological Association, American Foundation for Urological Disease and the Society for Basic Urological Research, as well as leaders in the field of endocrine research, and actively solicits the advice and input of these societies. Our planning process has also been carefully integrated with planning activities undertaken by NCI. A number of members of our investigative communities participated in the NCI Progress Review on Prostate Cancer, and the priority items in this plan are areas also identified as important in the Report of the Prostate Cancer Progress Review Group.
Directions
The discoveries that will lead to improved therapy and ultimately prevention and cure need to be sought through a number of avenues:
Prostate cancer typically develops in the setting of underlying benign prostatic disease. We need to understand more about the processes that cause growth of the prostate with age - and what this growth process has to do with malignant change.
The outcome of cancer depends not just on the behavior of the tumor cell - but also on the normal surrounding cells that are not themselves cancerous. We need to know more about the normal prostate cells - and the genes they express - in order to identify new targets for disease intervention. We also need to know more about the interactions between prostate cancer cells and bone, to understand the determinants of metastasis.
Developmental biology is proving to be an important source of clues about disease. We need to understand the developmental program for formation of the prostate and the lineage of the cells that make up the gland.
What is the action of androgen, the genes it controls and the mechanisms by which the hormone turns genes on and off? These are critical basic questions broadly anticipated to yield the basis for new therapeutic approaches.
We know too little about the variation in susceptibility of different populations to the disease of the prostate. Careful monitoring of epidemiological trends in the burden of benign and malignant prostate disease is an important priority. Particularly, the enhanced susceptibility of certain racial groups to prostate cancer - and the relative protection of other groups - are phenomena that we need to understand.
Better strategies to prevent the two feared complications of surgery on the prostate - urinary incontinence and impotence - are needed urgently. Although new surgical approaches for both benign prostatic hypertrophy and prostate cancer have reduced the rate of these complications, further progress is needed.
Prostate cancer is a hormone responsive tumor and the major forms of treatment of advanced prostate cancer involve pharmacologic blockade of the gonadatrophin release or antagonism of the androgen receptor. There are new and emerging opportunities to improve these approaches.
Five Year Prostate Research Plan
The NIDDK plans to expand substantially efforts in prostate research in 1999. Particular consideration will be given to full-funding of competing research project grants in the Institute's Urology and Endocrinology programs in areas that include:
Characterization of the cellular and molecular events that occur during prostate development;
Characterization--using array methods--of the patterns of gene expression in the prostate throughout the male life cycle, and during hyperplasia;
Targeted development of additional tools for study of prostate biology, such as identification of promoter sequences that dictate cell specific expression;
Expansion of support for development of surrogate markers, particularly characterization of proteins secreted by prostate tissues;
Expanded epidemiologic studies of prostate disorders in minority populations;
Identification of regulatory elements in androgen-regulated genes;
Elucidation of the mechanism of transactivation by ligand-bound androgen receptors;
Characterization of the growth factors critical for normal prostate tissue maturation and growth, and their contributions to tumor growth; and
Detailed studies of steroid metabolism in the prostate, centering on conversion of testosterone to dihydrotestosterone.
The Institute's George O'Brien Kidney and Urology Centers devoted to urology research, and one or two of the Kidney Centers with particular strength in genitourinary development, are being invited to prepare proposals for programs of pilot and feasibility projects in prostate biology.
The NIDDK also is supporting a study entitled "Chronic Prostatitis Collaborative Clinical Research Studies." This will be the first large, multicenter study designed to gather well-defined, detailed clinical information on the condition and then use that base to test and evaluate new treatment strategies in the future. The study will document symptoms, possible risk factors, medical histories and treatments; test blood, prostate fluid, semen and urine; and explore possible relationships between chronic prostatitis, urethral and bladder inflammation and other chronic pelvic pain disorders.
One of the NIDDK's existing George O'Brien Centers specializing in Urology is competing for renewal in 1999. The competition has resulted in receipt of five applications, which have not yet undergone review and received scores. If the proposals are excellent, the Institute may consider funding a second center beyond the one serving as a replacement.
Expansion of the Institute's urology epidemiology program is underway. An epidemiologist has just been recruited, and the NIDDK's epidemiology support contract will be doubled in size. Further expansion will continue in 2000, if it is deemed to be appropriate. A related effort to establish under contract a national database for clinical urology is expected to be awarded in 2000, and will be about one-half related to the prostate research.
Funds may be used to fund research project grants beyond the payline for new prostate projects in the Urology and Endocrinology Programs. Also, NIDDK staff are planning a special meeting of outside experts to discuss the most promising ongoing research projects that could benefit from supplementation. NCI staff are being invited to join in this meeting, together with prostate research leaders of their choice. There has also been a proposal for supplements to the clinical trial on Medical Treatment of Prostatic Symptoms to allow application of array methods to assess correlations in patterns of gene expression in tissue specimens with clinical outcomes in patients; this proposal will be further evaluated for possible funding in 1999 or 2000.
Training and manpower in investigative urology: The NIDDK plays a special role in fostering and supporting research training and manpower in investigative urology-both of clinical and basic investigators. Strengthened recruitment of investigators to study prostate cancer and enhanced support for career development are critical for the development of a national program on prostate cancer.
O'Brien Urology Centers: The NIDDK currently supports five George O'Brien Urology Research Centers. Some prostate cancer related work is performed in all of these centers, and three have a particular focus on the biology of the prostate.
The focus of the Center at the University of Washington is on prostate cancer, including how prostate cancer spreads to tissues beyond the prostate gland, the mechanisms that control the expression of prostate-specific antigen (PSA), development of research methods for gene therapy of prostate cancer, and interference with tumor progression, which may lead to treatments for prostate cancer.
The Center at the Sloan-Kettering Institute for Cancer Research is investigating regulatory mechanisms of prostate tumor progression, specifically the cellular changes that are associated with the progression of disease from normal to premalignant conditions.
The Center at The University of Texas Southwestern Medical School is examining several aspects of benign and malignant prostate growth, including the genetic alterations involved in prostate cancer, and the expression of male hormones in benign and malignant prostates.
In the current funding year, supplementary pilot and feasibility funds are being made available to these centers to develop new directions for work related to prostate cancer. Expansion of support for these centers in future fiscal years would be anticipated.
Targeted Areas of Scientific Emphasis
The following topic areas, all traditionally areas of strength in NIDDK, present opportunities for particular emphasis and expansion in this five-year plan. Each of these research avenues is described more fully in the following sections of this five-year Professional Judgment Report:
Clinical studies of the transition from benign to malignant prostate disease;
Cell and developmental biology of the normal prostate gland;
Epidemiology of prostate disease in minority populations;
Post-prostate-surgery urinary incontinence and impotence.
Prospective Clinical Studies of the Transition Between Benign Prostatic Hyperplasia and Prostate Cancer
Goals:
Define the effect of various strategies to treat benign prostatic hyperplasia on the incidence of prostate cancer;
Develop pathological criteria for sub-categorization of benign prostatic hyperplasia; examine correlations between molecular markers and pathological characteristics; establish the relative risk of prostate cancer associated with each sub-type;
Examine prospectively the prognosis of prostatic intraepithelial neoplasia (PIN);
Improve the accuracy of the diagnosis of early prostate cancer;
Test the predictive value of potential surrogate markers of prostate cancer;
Undertake systematic assessment of the patterns of gene expression in the prostate gland to define new molecular markers associated with enhanced susceptibility to prostate cancer and to define new molecular markers associated with the transition to malignant disease.
Elucidate further the detailed mechanisms of gonadotropin, androgen, and growth factor action on the prostate.
Implementation:
The NIDDK supports an extensive investigative program on treatment of benign disease of the prostate, especially, benign prostatic hyperplasia, BPH. A keystone of this program is an important clinical trial, the Medical Therapy of Prostate Symptoms (MTOPS), currently in its third year. MTOPS assesses the effect of two different pharmacological agents on the prevention of progression of symptomatic BPH and correlates those clinical effects with molecular and genetic actions on prostate biopsy tissue from participants in the study.
The study supports 19 clinical centers and has an enrollment of approximately 1,000 patients. It was developed with the principal goal of prospective, randomized evaluation of medical therapy for prostate symptoms, but has enormous potential for prospective evaluation of cancer risk. Patients are very carefully characterized and closely followed, with regular studies including stored plasma samples and repeat biopsies. All patients have undergone regular ultra-sound imaging using state of the art quantitative techniques.
Over the next ten years, a substantial portion of these patients are expected to develop prostate cancer. This cohort provides an extraordinary and very cost effective opportunity for studies to address the goals enumerated previously. We would plan to expand this cohort, and make it the basis for a major prospective epidemiology study with the goals listed above.
The following specific steps would be needed to fully implement this initiative:
Expand funding of MTOPS centers to expand the patient base and ensure the epidemiological expertise to achieve the goals listed previously;
Establish support for micro-array technology development and application of micro-array methods to stored patient biopsies;
Solicit investigator-initiated adjunctive studies utilizing the MTOPS patient population to evaluate surrogate markers and new diagnostic approaches.
Initiate clinical studies to determine the effectiveness of new prevention strategies.
Cell Biology and Developmental Biology of the Prostate Gland
Goals:
Define the cellular characteristics of the epithelial cells, stromal cells, endothelial cells, neuroepithelial cells and inflammatory cells that make up the prostate;
Define the specific interactions between these cells;
Develop a complete characterization of the biological processes in the prostate during its development, maturation and transition from normal to hyperplastic to malignant states;
Encourage investigation that utilizes these insights to define new therapeutic targets.
Implementation:
The NIDDK program in prostate biology and prostate growth provides a strong starting basis to build expanded investigation in these areas. Our advisory groups consistently recommend strong investment in the basic biology of the prostate gland as the best long-term strategy to identify breakthroughs in therapy, prevention and diagnosis of prostate cancer. Funding for this program in 1998 was approximately $5.0 million. Substantial expansion in each of the next fiscal years would be strongly justified scientifically by the scientific opportunities available in this area.
Most of the work on these topics is and will likely continue to be undertaken through investigator-initiated grants. Recently a program announcement, cosponsored with the NCI, was issued to stimulate submissions in these areas. A specific solicitation, focused on development of the prostate gland, is planned for 2000. Further steps to encourage investigation in these areas would include regular workshops and development of targeted research initiatives.
Mechanisms of Androgen Action
Goals:
Define the potential roles of androgen and critical other steroid hormones in prostate growth, tissue interactions and development;
Define the structure of androgen nuclear receptors;
Define the interacting proteins and the ligand-metabolizing enzymes in the prostate.
Implementation:
This important topic was identified as the number one priority in the Prostate Cancer Review Report by Subgroup A, Biology, Progression and Metastasis. It is widely recognized that the transition from androgen dependence to androgen independence is an absolutely critical event in the natural history of prostate cancer, and that this biological event often determines the patient prognosis. It is therefore critical that we develop a precise understanding of the process of androgen regulation of gene transcription.
As was recognized in the Prostate Cancer Review Group Report, this is an area traditionally supported by NIDDK, largely through investigator-initiated grants. Program initiatives over the next five years would undertake to encourage submissions in this area and to encourage investigators to examine these issues in prostate models. In addition, we would explore targeted strategies to expand translational and industry investment in these areas.
Epidemiology of Prostate Disease, Especially in Minority Men
Goals:
Define which segments of the U.S. population have enhanced or reduced susceptibility to benign prostatic hypertrophy and prostatitis, and the relationship between altered risk of benign disease and altered risk of prostate cancer;
Identify genetic and environmental factors associated with enhanced or reduced cancer risk, particularly in minority men.
Implementation:
Studies of prostate cancer have established that African American men are at increased risk, and suggest reduced risk in Americans with Asian backgrounds. There is less data on the relative risk for these populations of benign disease, or on the association between benign disease and cancer risk. In 1999, the NIDDK issued a Request for Proposals to establish a prospective epidemiology database of urologic disease. This study will use existing databases to examine a variety of associations and to obtain important descriptive parameters of urologic disease in the United States. This program will provide the infrastructure to address the issues defined above.
Complications of Surgery on the Prostate
Goals:
Define strategies to reduce the incidence of urinary incontinence and impotence after surgery
Develop new therapies and investigate efficacy of established therapies for these two surgical complications.
Implementation:
Better strategies are urgently needed to prevent the two feared complications of surgery on the prostate--urinary incontinence and impotence. Although new surgical approaches for both benign prostatic hypertrophy and prostate cancer have reduced the rate of these complications, further research is needed. Clinical and basic investigation in these two areas is a traditional strength of the programs supported by NIDDK. Creation of a clinical trials consortium to evaluate surgical outcome prospectively and rigorously, and to test new therapies would be encouraged in this area. A pilot phase would occur in 2000, with full implementation in 2001.
Training and Manpower Issues
Our advisory groups consistently identify a shortage of trained, experienced investigators in urology as an impediment to development of strong research in this area. The NIDDK has a strong program of support for training and career development in urology, but anticipates a need for substantial strengthening of this investment.
Programs would be developed to target the following needs:
Training of investigators with expertise in both clinical urology and in the design and implementation of clinical trials;
Recruitment of Ph.D. investigators from a variety of basic science disciplines to study of prostate cancer;
Development of careers of Ph.D. investigators.
Existing NIH training mechanisms, including the recently initiated awards for training of clinical investigators and mid-career investigators (K23 and K24), provide valuable approaches to these problems. NIDDK has also in the past utilized mechanisms of co-funding with non-profit foundations, for example NIH-AFUD fellowships, of training programs that would continue.
O'Brien Urology Centers
The NIDDK currently supports five George O'Brien Urology Research Centers. Some prostate cancer related work is performed in all of these centers, and three have a particular focus on the biology of the prostate.
Centers with a particular focus on prostate are as follows:
The Center at the University of Washington focuses on prostate cancer. This includes how prostate cancer spreads to tissues beyond the prostate gland, the mechanisms that control the expression of prostate-specific antigen (PSA), development of research methods for gene therapy of prostate cancer, and interference with tumor progression, which may lead to treatments for prostate cancer.
The Center at the Sloan-Kettering Institute for Cancer Research is investigating regulatory mechanisms of prostate tumor progression, specifically the cellular changes that are associated with the progression of disease from normal to premalignant conditions.
The Center at The University of Texas Southwestern Medical School is examining several aspects of benign and malignant prostate growth, including the genetic alterations involved in prostate cancer, and the expression of male hormones in benign and malignant prostates.
In the current funding year, supplementary pilot and feasibility funds are being made available to these centers to develop new directions for work related to prostate cancer. Expansion of support for these centers in future fiscal years would be anticipated.