BIOLOGY , DEVELOPMENT, AND PROGRESSION OF MALIGNANT PROSTATE DISEASE Release Date: April 8, 1999 PA NUMBER: PA-99-081 P.T. National Cancer Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Aging National Institute of Environmental Sciences PURPOSE The National Cancer Institute (NCI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Institute of Environmental Sciences (NIEHS) invite investigator-initiated research grant applications to examine a range of fundamental biological issues considered critical for progress in defeating prostate cancer. The purpose of this announcement is to encourage new projects focusing on the biology that underlies the development and progression of malignant prostatic disease. Multidisciplinary collaborations between basic and clinical scientists in projects ranging from exploratory basic biology studies to disease progression in appropriate biological systems or models are encouraged. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA,, Biology, Development, and Progression of Malignant Prostate Disease, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202- 512-1800), or on the Internet at the URL: http://www.crisny.org/health/us/health7.html ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Support of this program will be through individual research project grants (R01) and exploratory/developmental grants (R21). Beginning with the June 1, 1999 receipt date, "MODULAR GRANT APPLICATION AND AWARD" procedures will apply to all competing individual research project grants (R01), small grants (R03), and exploratory/developmental grants (R21) applications requesting up to $250,000 direct cost per year (see the NIH Guide, December 15, 1998). SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS are mentioned under APPLICATION PROCEDURES to reflect the process which has been adopted by the NIH. More detailed information about modular grant applications, including a sample budget narrative justification pages and a sample biographical sketch, is available via the Internet at url: http://www.nih.gov/grants/funding/modular/modular.htm BACKGROUND In the United States, prostate cancer has become the most frequently diagnosed neoplasm and the second leading cause of cancer mortality in men after lung cancer (SEER Prostate Cancer Trends, 1973-95 at http://seer.cancer.gov/Publications/ProstMono/. Its incidence rate has continued to increase rapidly during the past two decades especially in men over the age of 50 years, and 184,500 new incident cases were expected to be diagnosed in 1998. The incidence of prostate cancer increases with advancing age and with the present trend towards an aging population, its impact is a major public health concern. It is imperative therefore that we improve our understanding of the biology that underlies the growth and development of the normal and aging prostate as well as that which underlies the development and progression of prostatic disease. Prostate cancer originates as a localized lesion that subsequently progresses to acquire increased invasive, migratory and metastatic potentials. Our understanding of the underlying mechanisms that dictate prostate development, carcinogenesis, tumor progression, and metastatic dissemination is still rudimentary. The biochemical and molecular mechanisms that control cellular interaction during prostate organogenesis, morphogenesis, and functional differentiation remain undetermined. The differentiative and proliferative potential of prostatic stem cells have not been defined. The progression of prostate tumors from a localized disease probably occurs through alterations in proliferation, cell-cell adhesion, invasion potential, and critical interactions between the prostate cancer cells and surrounding host cells (stroma) at both primary and metastatic sites. Unfortunately, current methods of predicting how rapidly a given prostate cancer will acquire metastatic attributes, and progress from an androgen-dependent to an androgen- independent state are unreliable. The inter- and intra-cellular signaling pathways that govern androgen-receptor mediated gene transcription and also modulate other signal transduction pathways remain poorly characterized, and the specific target genes and gene products that are directly controlled by key signaling molecules during various stages of the prostate cancer development and progression have yet to be identified. Tumor-host interactions, pivotal to the mechanisms of cancer cell invasion, migration, and metastasis, are also poorly understood. Prostate cancer often metastasizes to the bone. Therefore, it is important to understand prostate cancer-skeletal interactions. It is critical to identify the molecular and biochemical features of bone physiology and pathophysiology that influence interaction between the prostate tumor and bone cells, and the subsequent characteristic osteoblastic reactions that are induced when tumor cells metastasize to the skeleton. To improve prevention, diagnosis, and treatment of prostate cancer, it is crucial to focus future research on the molecular, cellular, physiological, and pathological events that lead to uncontrolled growth and metastasis. RESEARCH OBJECTIVES Strengthening research programs of relevance to prostate cancer is an important area of emphasis for the National Cancer Institute (NCI), the National Institute of Diabetes, Digestive Disease and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Institute of Environmental Sciences (NIEHS). The National Cancer Institute established the Prostate Cancer Progress Review Group to help sharpen the focus of prostate research programs. This expert review group identified a broad range of fundamental biological issues of relevance to prostate cancer. The Review Group has helped the NIH define and prioritize the national research agenda for prostate cancer by identifying unmet scientific opportunities and providing expert opinions on how to hasten progress against the disease. This Program Announcement is in response to their recommendations. The Prostate Cancer Progress Review Group Report can be found at the following web site: http://www.nci.nih.gov - under :What's New. Understanding prostate cancer biology, progression and metastasis are fundamental to improving our abilities to successfully prevent, diagnose, and treat human prostate cancer. Among the areas encouraged by this PA are the analysis of the developmental, biological, and molecular genetic aspects of prostate disease, and the use of appropriate experimental models that mimic the clinical characteristics of prostate cancer growth, including acquisition of androgen-independence and the propensity to metastasize to bone. Also of particular interest are the identification of novel molecular and genetic markers associated with prostate development, carcinogenesis, tumor progression, and metastasis; the identification of the underlying mechanisms of racial differences in prostate cancer development and progression; the separation of indolent and virulent forms of disease; improvement in diagnosing and monitoring patients; and the potential to predict the ultimate malignant potential of a prostate tumor while it is still in a localized state. Additional areas of interest include studies to identify prostate cancer stem cells; elucidate the reciprocal interactions between the prostate tumor and host or bone cells; and define androgen receptor structure, function, and interaction with other cognate cell signaling molecules, transcriptional regulators, and cell-cell and cell-matrix intercommunication. Our ultimate goal is to better understand key concepts of prostate cancer biology, and identify means to exploit such information to prevent, diagnose, and treat prostate cancer. The following are examples of some of the areas of research recommended by the NCI Prostate Cancer Progress Review Group which are viewed as areas of high program relevance by the three participating institutes. Prostate Development, Morphogenesis and Hyperplasia: - What are the biochemical and molecular events that govern prostate development from early embryogenesis to the onset of adulthood, maturation, aging, and death? - What genes are directly regulated by androgen receptors during prostate development? - What other signaling pathways regulate prostate growth, development, differentiation, and apoptosis? - What is the nature of the stem cell for each of the prostate cell lineages? What are the steps in prostate-specific lineage specification, and what are the cellular signaling events that dictate this specification? Epithelial Cell-Stroma Interactions in the Developing, Normal, and Malignant Prostate: - What are the specific cell-cell interactions between and among developing epithelial cells,stromal cells, endothelial cells, neuroepithelial cells, and immune (myeloid and lymphoid) cells? - What are the regulatory effector molecules that control reciprocal interactions between epithelial and stromal cells, clonal interactions between cancer epithelial cells, and the interactions between cancer cells, and specific and non-specific cells of the immune system? Steroid Receptor Action and Metabolism: - What are the potential roles of nuclear receptors, their interactive proteins, and ligand-metabolizing enzymes on prostate growth, tissue interactions, and development? - How do cells survive in the prostate gland upon androgen withdrawal? - What are the molecular and cellular mechanisms that control the response of prostate cancer cells to alterations in androgens? - What is the mechanism by which androgen antagonists, such as flutamide, switch from inhibitors to enhancers of prostate cancer cell growth during systemic therapy? Novel Features in Prostate Cancer: DNA Damage/Repair or Cell Cycle: - Are there features of DNA damage, DNA repair, or cell cycle progression that are novel in prostate cancer cells? Cancer Progression: Tumor Angiogenesis, Invasion, and Metastasis: - What are the critical housekeeping and regulatory genes that may be associated with human prostate cancer development and progression? - What are the biological features of indolent and virulent prostate cancer? - Are there molecular determinants that cause progression from high grade prostatic intraepithelial neoplasia (PIN) to the malignant and metastatic phenotype? - Are there hereditary markers, angiogenesis switches, and/or biochemical and molecular determinants that predict progression? What are the molecular and cellular mechanisms that control cell signaling and its subsequent influence on cell motility, migration, angoigenesis and metastatic profiles? - What are the genetic and epigenetic determinants that affect progression of prostate cancer fromthe localized to disseminated state? What molecular markers are associated with suchp rogression? - What are the molecular determinants that govern cancer invasion, migration, and metastasis? - What characteristics of the tumor cells are responsible for the special affinity for bone and promote bone colonization? Can interactions between bone and prostate cancer cells be interrupted? - Can additional models be developed to specifically study cancer metastasis, particularly with respect to skeletal pathophysiology and its associated biochemical characteristics? - Are metastatic lesions in soft tissues (lymph nodes and lung metastases) phenotypically different from bone metastasis? - Can androgen-independent and metastatic phenotype be reversed? - What is the role of immune system in prostate cancer progression? The National Institute on Aging (NIA) The NIA supports and conducts research on the aging process, and age-related diseases. This includes research focused on underlying biologic mechanisms involved in the re-initiation of prostate growth in middle-aged men following post-pubertal quiescence with sustained growth in older ages, and in the relationship between this age-related growth process and the subsequent development of prostate cancer. Examples of research areas of interest to NIA which are related to this announcement include a) identification of prostate cell types, hormones and other bioregulatory factors, with timing processes and intracellular signaling pathways, that are involved in mid and late life prostate growth, b) the biological , molecular, cellular and genetic mechanisms, responsible for mid and late life prostate growth, and c) prostate developmental processes, and/or effects of hormones and other bioregulatory factors during development, that affects prostate growth in middle-aged and older men. Of particular interest is research addressing the underlying causes and biologic mechanisms responsible for racial/ethnic differences in prevalence of prostate cancer, particularly the increased prevalence in African American. The National Institute of Environmental Health Sciences (NIEHS) The NIEHS mission includes the support of research investigating the effects of chemical,physical and biological environmental agents on human health and well-being. A significant number of human diseases come about as a result of interactions between genetic factors and exposure to environmental factors over time associated periods of aging. The major goal of the NIEHS is to develop knowledge that will permit the better management of risks associated with living in an environment that includes exposures to environmental agents that induce adverse health effects. The NIEHS is interested in receiving investigator-initiated research grant applications to examine the role and mechanism of action of chemical, physical or biological environmental agents that adversely modify cellular, molecular, and/or physiological events associated with the growth and development of the normal, aging, and neoplastic prostate gland. In particular, studies on environmental agent exposure(s) that may be associated with altered programs of gene expression for mechanisms associated with the induction or progression of premalignant or malignant prostate disease are sought. Such studies would elucidate and delineate intervention principles for the prevention of environmentally- related disease as well as for protective actions by regulatory agencies. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. Since this PA focuses on prostate cancer, which only occurs in men, the required inclusion of women does not apply. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://www.nih.gov/grants/guide/notice-files/not98-024.html As part of the scientific and technical merit evaluation of the research plan, reviewers will be instructed to address: Adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion. Since this PA focuses on prostate cancer, which only occurs in men, the required inclusion of children does not apply. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, E- mail: grantsinfo@nih.gov. The title and number of the announcement must be typed in Section 2a on the face page of the application. The yes box must be marked. For those applicants with internet access, the 398 kit may be found at http://www.nih.gov/grants/funding/phs398/forms_toc.html Any applicant planning to submit an investigator- initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year is advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and contracts, March 20, 1998 at http://www.nih.gov/grants/guide/notice-files/not98-030.html. The completed original application and five legible copies must be sent or delivered to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 - MSC 7710 Bethesda, MD 20892-7710 (20817 for express service) SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS These instructions apply to applications requesting up to $250,000 direct cost per year. o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page. (See http://www.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://www.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List current position(s) and then previous positions; - List selected peer-reviewed publications, with full citations; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. Applications requesting upto $250,000 direct cost per year and not conforming to these guidelines will be considered unresponsive to this PA and will be returned without further review. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the Center for Scientific Review (CSR) for completeness. Incomplete applications will be returned to the applicant without further consideration. Those applications judged to be complete will be further evaluated for scientific and technical merit by appropriate Study Sections in CSR in accordance with standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Preliminary data will not be required for R21 applications. The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that IC. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Suresh Mohla, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Room 505 Rockville, MD 20852-7385 (T) (301) 496-7028 (F) (301) 402-1037 (E) sm82e@nih.gov Leroy M. Nyberg, Jr., Ph.D., M.D. Director, Urology Programs DKUHD/NIDDK/NIH Bldg 45, Room 6AS-13 (T) 301-594-7717 (F) 301-480-3510 (E) leroy_nyberg@nih.gov Frank Bellino, Ph.D. Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892-9205 (T (301) 496-6402 (F) (301) 402-0010 (E) fb12a@nih.gov Michael E. McClure, Ph.D. Chief, Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences, NIH 111 T.W. Alexander Drive Courier: 79 P.O. Box 12233, Mail Drop EC-23 Bldg. 4401, Rm. 3417 Research Triangle Park, North Carolina 27709 RTP. NC 27709 (T) (919) 541-5327 (F) (919) 541-5064 (E) mm461n@nih.gov Direct inquiries regarding fiscal matters to: Michelle Burr Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 242 Rockville, MD 20892- (T) (301) 496-7800 (F) (301) 496-8601 (E) Burrm@gab.nci.nih.gov Trude Hilliard Grants Management Specialist GMB/NIDDK/NIH Bldg 45, Room 6AN-44B 6600 Center Drive Bethesda, MD 20892-6600 (T) 301-594-8859 (F) 301-480-3504 (E) HilliardT@extra.niddk.nih.gov Bob Pike Grants Management Office National Institute on Aging Gateway Building, Suite 2N212 Bethesda, MD 20892-9205 (T) (301) 496-1472 (F) (301) 402-3672 (E) pikeb@exmur.nia.nih.gov David Mineo Grants Management Officer National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-22 111 T.W. Alexander Drive, East Campus Research Triangle Park, NC 27709 (T) (919) 541-1373 (F) (919) 541-1373 (E) mineo@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.396, 93.866, 93.113.93.854 and 93.242. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act, as amended ( 42 USC 241 and 284) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and part 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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