MOLECULAR TARGETS FOR NUTRIENTS IN PROSTATE CANCER PREVENTION RELEASE DATE: April 24, 2003 RFA: CA-04-004 National Cancer Institute (NCI) (http://www.nci.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: No. 93.393 LETTER OF INTENT RECEIPT DATE: June 19, 2003 APPLICATION RECEIPT DATE: July 17, 2003 This RFA is a reissue of RFA-CA-03-003, which was published in the NIH Guide on February 13, 2002. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE The Division of Cancer Prevention, National Cancer Institute (NCI), invites applications for new R01 grants to foster probing investigations that will define molecular targets for nutrients and further, connect those targets with phenotypic outcome in prostate cancer prevention. Candidate targets for examination should not only be influenced by a nutrient but also be closely linked to a significant proportion of prostate tumors, be relatively specific for prostate cancer across various genetic backgrounds, and be related to changes in tumor risk and/or behavior when modified. Investigators are encouraged to use in vitro and in vivo studies with various levels of target expression and to address confounding factors that influence the overall physiological response to changes in a given molecular target. RESEARCH OBJECTIVES Background Although the etiology of prostate cancer is poorly understood, a variety of dietary components spanning the gamut of essential and non-essential nutrients are proposed to influence prostate cancer risk. The impact of specific dietary components on prostate tissue likely depends on a host of genetic and epigenetic processes that influence growth, development, and differentiation. Phenotypic changes may arise directly from alterations in specific genetic and/or epigenetic events or indirectly from changes in hormonal balance, immunocompetence, or the activity of other bioregulators. Possible Molecular Targets for Nutrients Advances in biology have identified several regulatory sites that may serve as potential molecular targets for prostate cancer prevention. Evidence already exists that nutrients may alter prostate cancer risk and tumor cell behavior by influencing hormonal regulation, cell signaling, cell cycle control, apoptosis, differentiation, and carcinogen metabolism. 1. Hormonal Regulation Factors involved in hormonal regulation may serve as targets since sex hormones are known to have a pivotal role in growth, differentiation, and function of prostate tissue. One of the central elements of hormonal regulation is the androgen receptor (AR), a member of the superfamily of nuclear receptors. The transcriptional activation domain of the androgen receptor gene contains a polymorphic CAG repeat sequence. Variability in the length of this sequence is recognized to influence the transcriptional activity of the androgen receptor. Men with shorter CAG repeats have been reported to be more androgen sensitive and to have a high risk for distant metastatic and fatal prostate cancer. Varying lengths of CAG-repeats of the androgen receptor do not appear to fully explain racial differences in clinical prostate cancer incidence suggesting other factors such as diet may be involved. Evidence for a role of diet comes from observations that caloric restriction reduces the loss of hepatic AR mRNA levels caused by aging. Resveratrol, found in grapes and peanuts, was also shown to repress the expression of AR, which in turn lowered the levels of prostate-specific antigen (PSA) and p21(WAF1). Expanding these findings to several factors influencing other processes of prostate cancer cells will clarify if AR can serve as a molecular target or surrogate marker for nutrients. In some experimental models, androgen deprivation results in a spontaneous increase in estrogen receptor (ER) expression in prostatic tissue. Estrogen receptor has two subtypes, alpha and beta. ER alpha and ER beta were shown to signal in opposite ways when complexed with the natural ligand, 17 beta- estradiol from an AP1 site. Prostate cells express ER beta abundantly, not ER alpha while uterine cells express ER alpha dominantly. ER beta from the prostate has a high affinity for genistein, a major soy isoflavone, which has several biological effects including a protein tyrosine kinase (PTK) inhibitor, an antioxidant, an inhibitor of angiogenesis, a blocker of topoisomerase II, an arrester of the cell cycle at the G2/M stage as well as acting as a phytoestrogen. This phytochemical has been shown to inhibit the growth of LNCaP human prostatic cancer cells in culture (IC50 = 50 ?M). It also has been shown to reduce one of the most fundamental biomarkers for prostate cancer, PSA, as well as modulate other proliferation and cell cycle related factors including PCNA, p21 (WAF1) and p27 (Kip1). Further studies are needed to determine which of these molecular targets is primarily responsible for genistein's antiproliferative effects on prostate cancer cells. 2. Cell Signaling Cells are constantly responding to numerous extracellular signals and coordinating these complex messages into a collection of responses that may be modulated by dietary components. One critical aspect of intracellular signaling is regulation of key cell functions by lipid mediators, particularly phosphatidylinositol (PI). Evidence already exists that the composition of membrane PI that is closely linked to phosphatidylinositol 3- kinase (PI3K) signaling pathway, depends on dietary lipids. More specifically, increased prostate cancer cell proliferation and prolongation of survival has been observed following linoleic and arachidonic acid treatment of cells in culture. Enhanced PI3K activity through hydroxyeicosatetraenoic acid (HETE) and prostaglandin E2 formation may relate to this elongated cancer cell survival. Genistein is known to inhibit growth factor receptors that lie upstream from the PI3K signaling pathway, which may account for the growth suppressive effect of this soy component. Evidence from these studies may explain the observations that consumption of a low fat diet supplemented with soy protein and isoflavonoids markedly retards the growth of the human androgen-sensitive prostate cancer cells (LNCaP) transplanted in severe-combined immunodeficient (SCID) mice. PI3K is also important in the Akt/PKB pathway that is initiated by survival factors including insulin-like growth factor I (IGF-I). Evidence exists that circulating blood levels of IGF-I decrease with increased blood lycopene, a dietary antioxidant found in red tomatoes. This finding is consistent with data from the Physicians Health Study that indicated an inverse relationship between circulating blood levels of lycopene and aggressive prostate cancer incidence. More probing studies will delineate the dynamics among nutrients that modulate cell signaling pathway. 3. Apoptosis/Cell Cycle Apoptosis, also known as programmed cell death, is one of the important pathways through which nutrients can inhibit the growth of cancer cells. This pathway is regulated by the Bcl2 gene family that contains individual members that can suppress (e.g. Bcl2) or promote (e.g. Bax) cell death. While this process is very complex, part of apoptosis can be mediated by deregulation in cell cycle progression that is governed by a family of cyclin-dependent kinases (CDKs). Evidence exists that a variety of nutrients modulate a number of genes or gene products that are involved in this process. For example, (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, imparted apoptotic effects against human prostate cancer cells by up-regulating CDK inhibitors including p21(WAF1) and p27(Kip1) with the concomitant increase in Bax and the decrease in Bcl2 levels. Similar effects of this phytochemical were demonstrated in transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic prostate cancer. In this study oral administration of green tea polyphenols caused significant apoptosis of prostate cancer cells, which possibly resulted in several phenotypic changes including significant delay in primary tumor incidence as assessed by magnetic resonance imaging (MRI), almost complete inhibition of distant site metastases, and significant decrease in prostate weight compared with water- fed TRAMP mice. Other evidence for the involvement of nutrients in this pathway comes from the treatment of prostate cancer cells with indole-3- carbinol, a component of cruciferous vegetables. When PC3 cells were supplemented with indole-3-carbinol, cells were arrested at the G1 cell cycle with the up-regulation of p21(WAF1) and p27(Kip1), accompanied with the increased Bax and the decreased Bcl2 levels. While these findings support the epidemiologic observations that green tea and cruciferous vegetables may reduce prostate cancer risk in humans, more probing studies are needed to determine the molecular targets for these dietary constituents. 4. Differentiation Vitamin A and D receptors, ligand-inducible nuclear transcription factors, have an important function to promote differentiation in various cells. Polymorphism in the vitamin D receptor (VDR) gene has been linked with prostate cancer risk. Adding 1,25-dihydroxyvitamin-D3 (1,25 D) inhibits the growth of primary cultured human prostatic cells, and their invasion. These effects may relate to changes in surface adhesion molecules or to other biological events. Since the VDR heterodimerizes with the retinoid X receptor, the intake of retinoids and carotenoids may also influence the overall response. Currently, insufficient information exists about the influence of vitamin A or vitamin D binding to normal or polymorphic receptors on transcriptional regulation and the subsequent modulation of cell growth and invasion of prostate cancer cells. The inverse relationship between calcium intake and blood levels of the 1,25- D suggests that high calcium intake may increase prostate cancer risk. Ecologic data support this hypothesis. The biological basis for this observation remains to be determined. Examination of genes involved with calcium channels or other calcium sensitive pathways may help explain the role of this nutrient in prostate cancer development. 5. Carcinogen Metabolism Accumulating research suggests that normal prostate cells are sensitive to genome-damaging carcinogens. For example, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen present in well-done meat that has been reported to increase prostate cancer in rats. Bioactivated PhIP exerts its mutagenic and carcinogenic effects by causing DNA damage in several tissues including prostate. Recent experimental evidence demonstrated that induction of glutathione S- transferase pi (GSTP1), a major class of GSTs, protected cells against PhIP induced DNA damage in human prostate cancer cells (LNCaP). GSTP1 expression is silenced by the methylation process in prostatic adenocarcinoma and high- grade prostatic intraepithelial neoplasia (HGPIN). What impact dietary methyl donors have on the GSTP1 methylation and the subsequent carcinogen detoxification in prostate cancer remains to be determined. Animal Models Offer Unique Possibilities The frequency of spontaneous prostate cancer is rare in mammals except for humans and dogs. Carcinogen or transgenic models that provide some clues about preventative and therapeutic strategies have been developed. During the past decade the Lobund-Wistar rats have been used as a model since they exhibit prostatic intraepithelial neoplasia and are predisposed to metastasizing adenocarcinomas following treatment with methylnitrosourea. The supplementation with phytochemicals, such as genistein, has been reported to lower tumors in this model. More recently a variety of genetically defined mice, including transgenics and gene knockouts, have been developed, which display prostatic hyperplasia and dysplasia. The availability of these mice may provide an important tool for characterizing molecular targets for nutrients. Recent studies demonstrate that a low saturated fat diet or supplementation with green tea polyphenols suppress tumor incidence and metastasis in the TRAMP model. Knockout animals are beginning to be used to examine genes that may influence the ability of nutrients and/or drugs to alter the cancer process. For example, 1,2-dithiole-3-thione found in alliaceous and cruciferous plants is known to be a potent inhibitor of chemically induced tumors. The molecular target for this compound became clearer as a result of recent studies using an nrf2 knockout mouse model. Induction of several phase II enzymes by 1,2- dithiole-3-thione was completely abrogated in nrf2 knockout mice treated with model carcinogens. The expanded use of animal models should provide unique opportunities for explaining the impact of individual dietary components on the observed variation in prostate cancer incidence. Objectives and Scope This Request for Applications (RFA) seeks to promote research to clarify the molecular basis by which nutrients retard prostate cancer. Connecting molecular targets for nutrients with phenotypic outcome offers the exciting opportunity for basic research and for explaining variation in observed responses within and across populations and hopefully for those who will benefit most from dietary intervention strategies. The object of this RFA is to identify and characterize molecular targets for nutrients in normal and neoplastic prostate cells. Since targets are not static but dynamic processes that must be examined over a full range of expression, investigators are encouraged to use various levels of target expression to determine the precise role of nutrients in prostate cancer prevention. Nutrients may modify simultaneously more than one process including carcinogen metabolism, hormonal balance, cell signaling, cell cycle control, apoptosis, and differentiation. Therefore, it is important that an integrative approach is taken to these investigations. Investigators are encouraged to address confounding factors that may influence the overall physiological response to changes in a given molecular target. For example alterations in p27(Kip1) that arise from direct or indirect interactions with nutrients may bring about fluctuations in various factors in signaling pathways such as protein tyrosine kinases, survival pathways such as IGF- 1/PI3K/Akt, oncogenes including c-myc, tumor suppressor genes including pRb, apoptosis related genes including Bcl2, cell senescence including telomerase activity, and inflammation related transcription factors including NF-kappaB. Several nutrients may modify the same target. For example, p27(Kip1) could be a potential molecular target for various nutrients including genistein, EGCG, indole 3-carbinol, and resveratrol. Investigators will be encouraged to define nutrients in terms of their relative effectiveness, dose- dependency, temporality, consistency, and specificity. The use of chemically induced, transgenic, and knockout animal models offers additional opportunities for unraveling the specific role of nutrients beyond that possible when cell culture systems are used. The use of transgenic and/or conditional knockout models available through the Mouse Models for Human Cancer Consortium (MMHCC, http://emice.nci.nih.gov/) is encouraged. For example studies that examine the impact of suppressed or exaggerated activities of genes regulating nutrient absorption or metabolism may provide clues to variation in response. Additionally, transcriptional factors, cofactors and other regulators that influence a specific target may be appropriate for manipulation in chemically induced or transgenic models used to define the role of nutrients. The use of a variety of molecular technologies including genetic manipulation of animal models, cDNA/tissue microarray, serial analysis of gene expression (SAGE), and proteomic tools are encouraged. Investigators are encouraged to utilize NCI's Cancer Genome Anatomy Project database on human and mouse genomics including expressed sequence tags (ESTs), gene expression patterns, single nucleotide polymorphisms (SNPs), cluster assemblies, and cytogenetic information (http://cgap.nci.nih.gov/). The following are viewed as relevant examples for the development of the R01 application. Note that these are examples only and are not intended to be inclusive. 1) Can variation in AR or ER explain the ability of soy isoflavones to retard prostate cancer? 2) Can IGF-1, PI3K, and Akt account for the effect of dietary fatty acids on prostate tumor growth promotion? 3) Are Bax and Bcl2 responsible for the efficacy of green tea polyphenols and indole 3 carbinol to retard prostate cancer cell growth? 4) Does modification of antioxidant response element (ARE) explain the ability of dietary antioxidants to reduce prostate cancer incidence? 5) Can GSTP1 methylation be influenced by dietary methyl donors and ultimately modify prostate cancer risk? RESEARCH REQUIREMENTS Applications in response to the RFA must address the following areas: (a) The effects of nutrients on growth and survival in prostate cancer cells will need to be characterized in terms of dose-dependency and temporality. (b) Targets for these nutrients should be examined over a range of expression, ideally from null to overexpression. MECHANISM OF SUPPORT This RFA will use NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The anticipated award date is April 1, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE NCI intends to commit approximately $2.5 million in FY 2004 to fund 4 to 6 new grants in response to this RFA. An applicant may request a project period of up to 5 years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Dr. Young S. Kim Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., Room 3156 Bethesda, MD 20892 Telephone: (301) 496-0126 FAX: (301) 480-3925 Email: yk47s@nih.gov o Direct inquiries regarding peer review issues to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 Telephone (301) 496-3428 Fax: (301) 402-0275 Email: ncirefof@dea.nci.nih.gov o Direct inquiries regarding fiscal matters to: Ms. Kathryn Dunn Grants Administration Branch National Cancer Institute 6120 Executive Plaza South, Room 243 Bethesda, MD 20892 (For Express mail, use Rockville, MD 20852) Telephone: (301) 846-8629 FAX: (301) 846-5720 Email: dunnk@gab.nci.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dr. Young S. Kim Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., Room 3156 Bethesda, MD 20892 Rockville, MD 20852 (express courier) Telephone: (301) 496-0126 FAX: (301) 480-3925 Email: yk47s@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001, http://grants.nih.gov/grants/funding/phs398/phs398.html) includes step-by- step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/01) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO NIH: Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/ NOT-CA-02-002.html) This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received on or before July 17, 2003. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NCI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities (DEA) at NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score. o Receive a second level review by the National Cancer Advisory Board (NCAB). REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address linkages between molecular targets for nutrients and phenotypic outcome in prostate cancer? If the aims of the application are achieved, how will the nutrients that modify specific molecular targets be used for dietary intervention studies in prostate cancer? Will these research projects advance the field of nutrition from observational to more probing studies? APPROACH: Are the conceptual framework, design, methods, and analyzes adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the applicant propose to study various levels of target expression to determine the precise role of nutrients in prostate cancer prevention? Does the applicant plan to examine the effects of nutrients on candidate targets using in vivo system? Does the applicant propose to characterize the temporal and dose effects of nutrient(s) on their molecular targets? 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? 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)? 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt: June 19, 2003 Application Receipt: July 17, 2003 Peer Review Date: November/December, 2003 Review by NCAB Advisory Board: February 2004 Earliest Anticipated Start Date: April 01, 2004 AWARD CRITERIA Applications recommended by the National Cancer Advisory Board will be considered for award based upon the following: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_ amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 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 is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research is available online at: http://cme.nci.nih.gov/ HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93. 393 (Cancer Cause & Prevention Research at, http://www.cfda.gov) and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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